Poly(oxazoline-co-ethyleneimine)-epichlorohydrin copolymers and uses thereof

ABSTRACT

The invention is related to poly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymers and chemically-modified derivatives thereof as well as their uses in formation of non-silicone hydrogel coatings on silicone hydrogel contact lenses.

This application claims the benefits under 35 USC §119 (e) of U.S.provisional application No. 62/041,762 filed 26 Aug. 2014, incorporatedby reference in its entirety.

The present invention generally relates topoly(2-oxazoline-co-ethylenimine)-epichlorohydrin copolymers andchemically-modified derivatives thereof suitable for applying a hydrogelcoating onto a silicone hydrogel contact lens in a cost-effective andtime-efficient manner. In addition, the present invention provides anophthalmic lens product.

BACKGROUND

Soft silicone hydrogel contact lenses are increasingly becoming popularbecause of their high oxygen permeability and comfort. But, a siliconehydrogel material typically has a surface, or at least some areas of itssurface, which is hydrophobic (non-wettable) and susceptible toadsorbing lipids or proteins from the ocular environment and may adhereto the eye. Thus, a silicone hydrogel contact lens will generallyrequire a surface modification.

A known approach for modifying the hydrophilicity of a relativelyhydrophobic contact lens material is through the use of a plasmatreatment, for example, commercial lenses such as Focus NIGHT & DAY™ andO2OPTIX™ (CIBA VISION), and PUREVISION™ (Bausch & Lomb) utilize thisapproach in their production processes. Advantages of a plasma coating,such as, e.g., those may be found with Focus NIGHT & DAY™, are itsdurability, relatively high hydrophilicity/wettability), and lowsusceptibility to lipid and protein deposition and adsorption. But,plasma treatment of silicone hydrogel contact lenses may not be costeffective, because the preformed contact lenses must typically be driedbefore plasma treatment and because of relative high capital investmentassociated with plasma treatment equipment.

Various other approaches are proposed and/or used for modifying thesurface hydrophilicity of a silicone hydrogel contact lens. Examples ofsuch other approaches include incorporation of wetting agents(hydrophilic polymers) into a lens formulation for making the siliconehydrogel contact lens (see, e.g., U.S. Pat. Nos. 6,367,929, 6,822,016,7,052,131, and 7,249,848); a layer-by-layer (LbL) polyionic materialdeposition technique (see, e.g., U.S. Pat. Nos. 6,451,871; 6,719,929;6,793,973; 6,884,457; 6,896,926; 6,926,965; 6,940,580; and 7,297,725,and U.S. Pat. Appl. Pub. Nos. 2007/0229758A1; 2008/0174035A1 and2008/0152800A1); crosslinking of LbL coatings on contact lenses has beenproposed in commonly-owned copending US pat. Appl. pub. Nos.2008/0226922 A1 and 2009/0186229 A1; and attachment of hydrophilicpolymers onto contact lenses according to various mechanisms (see forexample, U.S. Pat. Nos. 6,099,122, 6,436,481, 6,440,571, 6,447,920,6,465,056, 6,521,352, 6,586,038, 6,623,747, 6,730,366, 6,734,321,6,835,410, 6,878,399, 6,923,978, 6,440,571, and 6,500,481, US Pat. Appl.Pub. Nos. 2009/0145086 A1, 2009/0145091A1, 2008/0142038A1, and2007/0122540A1). Although those techniques can be used in rendering asilicone hydrogel material wettable, there are some shortcomings inthose techniques. For example, wetting agents may impart haziness to theresultant lenses because of their incompatibility with other siliconecomponents in the lens formulation and may not provide a durablehydrophilic surface for extended wear purposes. LbL coatings may not beas durable as plasma coatings and may have relatively high densities ofsurface charges; which may interfere with contact lens cleaning anddisinfecting solutions. Crosslinked LbL coatings may have ahydrophilicity and/or wettability inferior than original LbL coatings(prior to crosslinking) and still have relative high densities ofsurface charges. In addition, they may not be cost-effective and/ortime-efficient for implementation in a mass production environment,because they typically require relatively long time and/or involvelaborious, multiple steps to obtain a hydrophilic coating.

Recently, a new cost-effective approach has been described in U.S. Pat.No. 8,529,057 (herein incorporated by reference in its entirety) forapplying a non-silicone hydrogel coating onto a silicone hydrogelcontact lens. It discloses that a partially-crosslinked hydrophilicpolymeric material derived from a polyamidoamine epichlorohydrin (PAE)and a wetting agent are used in the formation of non-silicone hydrogelcoating on a contact lens. Although this new approach can providesilicone hydrogel contact lenses with durable hydrophilic coatingsthereon, its applicability and advantages can be limited by the lack ofversatility and controllability in the levels of hydrophilicity and/orreactive functional group contents of the partially-crosslinkedhydrophilic polymeric material.

Therefore, there is still a need for reactive copolymers having desiredlevel of hydrophilicity and/or functional groups content for applying anon-silicone hydrogel coating onto a silicone hydrogel contact lens.

SUMMARY OF THE INVENTION

The invention, in one aspect, provides apoly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer comprising:from about 2% to about 95% by mole of N-acyl-iminoethylene monomericunits; from about 0.5% to about 95% by mole of azetidinium monomericunits; from 0 to about 60% by mole of ethylenimine monomeric units; andfrom 0 to about 5% by mole of crosslinking units, relative to the totalcomposition of the poly(2-oxazoline-co-ethyleneimine)-epichlorohydrincopolymer.

The invention, in another aspect, provides a water-soluble andthermally-crosslinkable hydrophilic polymeric material which comprises:azetidinium groups; from about 20% to about 95% by weight of firstpolymer chains derived from apoly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer of theinvention; and from about 5% to about 80% by weight of hydrophilicmoieties or second polymer chains derived from at least onehydrophilicity-enhancing agent having at least one reactive functionalgroup selected from the group consisting of primary amino group,secondary amino group, carboxyl group, thiol group, and combinationthereof.

The invention, in a further aspect, provides methods for producingcoated silicone hydrogel contact lenses each having a crosslinkedhydrophilic coating thereon, involving use of at least apoly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer of theinvention fully described above and/or at least one water-soluble andthermally crosslinkable hydrophilic polymeric material of the inventionfully described above.

These and other aspects of the invention will become apparent from thefollowing description of the presently preferred embodiments. Thedetailed description is merely illustrative of the invention and doesnot limit the scope of the invention, which is defined by the appendedclaims and equivalents thereof. As would be obvious to one skilled inthe art, many variations and modifications of the invention may beeffected without departing from the spirit and scope of the novelconcepts of the disclosure.

DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Generally, the nomenclatureused herein and the laboratory procedures are well known and commonlyemployed in the art. Conventional methods are used for these procedures,such as those provided in the art and various general references. Wherea term is provided in the singular, the inventors also contemplate theplural of that term. The nomenclature used herein and the laboratoryprocedures described below are those well-known and commonly employed inthe art.

“About” as used herein means that a number referred to as “about”comprises the recited number plus or minus 1-10% of that recited number.

An “ophthalmic device”, as used herein, refers to a contact lens (hardor soft), an intraocular lens, a corneal onlay, other ophthalmic devices(e.g., stents, glaucoma shunt, or the like) used on or about the eye orocular vicinity.

“Contact Lens” refers to a structure that can be placed on or within awearer's eye. A contact lens can correct, improve, or alter a user'seyesight, but that need not be the case. A contact lens can be of anyappropriate material known in the art or later developed, and can be asoft lens (e.g., hydrogel lens or silicone hydrogel lens), a hard lens,or a hybrid lens. A “silicone hydrogel contact lens” refers to a contactlens comprising a silicone hydrogel bulk (core) material.

A “hydrogel” or “hydrogel material” refers to a crosslinked polymericmaterial which is insoluble in water, but can absorb at least 10 percentby weight of water when it is fully hydrated.

A “silicone hydrogel” refers to a silicone-containing hydrogel obtainedby copolymerization of a polymerizable composition comprising at leastone silicone-containing monomer or at least one silicone-containingmacromer or at least one crosslinkable silicone-containing prepolymer.

As used in this application, the term “non-silicone hydrogel” refers toa hydrogel that is theoretically free of silicon.

“Hydrophilic,” as used herein, describes a material or portion thereofthat will more readily associate with water than with lipids.

A “vinylic monomer” refers to a compound that has one sole ethylenicallyunsaturated group, is soluble in a solvent, and can be polymerizedactinically or thermally.

The term “soluble”, in reference to a compound or material in a solvent,means that the compound or material can be dissolved in the solvent togive a solution with a concentration of at least about 0.5% by weight atroom temperature (i.e., a temperature of about 22° C. to about 28° C.).

The term “insoluble”, in reference to a compound or material in asolvent, means that the compound or material can be dissolved in thesolvent to give a solution with a concentration of less than 0.005% byweight at room temperature (as defined above).

As used in this application, the term “ethylenically unsaturated group”is employed herein in a broad sense and is intended to encompass anygroups containing at least one >C═C< group. Exemplary ethylenicallyunsaturated groups include without limitation (meth)acryloyl

allyl, vinyl, styrenyl, or other C═C containing groups.

The term “(meth)acrylamide” refers to methacrylamide and/or acrylamide.

The term “(meth)acrylate” refers to methacrylate and/or acrylate.

As used herein, “actinically” in reference to curing, crosslinking orpolymerizing of a polymerizable composition, a prepolymer or a materialmeans that the curing (e.g., crosslinked and/or polymerized) isperformed by actinic irradiation, such as, for example, UV/visibleirradiation, ionizing radiation (e.g. gamma ray or X-ray irradiation),microwave irradiation, and the like. Thermal curing or actinic curingmethods are well-known to a person skilled in the art.

A “hydrophilic vinylic monomer”, as used herein, refers to a vinylicmonomer which as a homopolymer typically yields a polymer that iswater-soluble or can absorb at least 10 percent by weight of water.

A “hydrophobic vinylic monomer”, as used herein, refers to a vinylicmonomer which as a homopolymer typically yields a polymer that isinsoluble in water and can absorb less than 10 percent by weight ofwater.

A “macromer” or “prepolymer” refers to a compound or polymer thatcontains ethylenically unsaturated groups and has an average molecularweight of greater than 700 Daltons.

As used in this application, the term “vinylic crosslinker” refers to acompound having at least two ethylenically unsaturated groups. A“vinylic crosslinking agent” refers to a vinylic crosslinker having amolecular weight of 700 Daltons or less.

As used in this application, the term “polymer” means a material formedby polymerizing/crosslinking one or more monomers or macromers orprepolymers or combinations thereof.

As used in this application, the term “molecular weight” of a polymericmaterial (including monomeric or macromeric materials) refers to theweight-average molecular weight unless otherwise specifically noted orunless testing conditions indicate otherwise.

A “polysiloxane” refers to a compound containing a polysiloxane segmentof

in which m1 and m2 independently of each other are an integer of from 0to 500 and (m1+m2) is from 2 to 500, R₁′, R₂′, R₃′, R₄′, R₅′, R₆′, R₇′,and R₈′ independently of one another, are C₁-C₁₀ alkyl, C₁-C₄ alkyl- orC₁-C₄- alkoxy-substituted phenyl, C₁-C₁₀ fluoroalkyl, C₁-C₁₀fluoroether, C₆-C₁₈ aryl radical, -alk-(OC₂H₄)_(m3)—OR′ (in which alk isC₁-C₆ alkyl diradical, a is H or C₁-C₄ alkyl and m3 is an integer from 1to 10), or a linear hydrophilic polymer chain.

A “polycarbosiloxane” refers to a compound containing apolycarbosiloxane segment of

in which n1 is an integer of 2 or 3, n2 is an integer of from 2 to 100(preferably from 2 to 20, more preferably from 2 to 10, even morepreferably from 2 to 6), R₁″, R₂″, R₃″, R₄″, R₅″, and R₆″ independent ofone another are a C₁-C₆ alkyl radical (preferably methyl).

The term “fluid” as used herein indicates that a material is capable offlowing like a liquid.

The term “alkyl” refers to a monovalent radical obtained by removing ahydrogen atom from a linear or branched alkane compound. An alkyl group(radical) forms one bond with one other group in an organic compound.

The term “alkylene divalent group” or “alkylene diradical” or “alkyldiradical” interchangeably refers to a divalent radical obtained byremoving one hydrogen atom from an alkyl. An alkylene divalent groupforms two bonds with other groups in an organic compound.

The term “alkyl triradical” refers to a trivalent radical obtained byremoving two hydrogen atoms from an alkyl. An alkyl triradical formsthree bonds with other groups in an organic compound.

The term “alkoxy” or “alkoxyl” refers to a monovalent radical obtainedby removing the hydrogen atom from the hydroxyl group of a linear orbranched alkyl alcohol. An alkoxy group (radical) forms one bond withone other group in an organic compound.

In this application, the term “substituted” in reference to an alkyldiradical or an alkyl radical means that the alkyl diradical or thealkyl radical comprises at least one substituent which replaces onehydrogen atom of the alkyl diradical or the alkyl radical and isselected from the group consisting of hydroxy (—OH), carboxy (—COOH),—NH₂, sulfhydryl (—SH), C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ alkylthio(alkyl sulfide), C₁-C₄ acylamino, C₁-C₄ alkylamino, di-C₁-C₄ alkylamino,halogen atom (Br or CI), and combinations thereof.

In this application, an “oxazoline” refers to a compound of

in which R¹ is hydrogen, C₁-C₁₈ alkyl, C₁-C₄ alkyl- substituted phenyl,C₁-C₄-alkoxy-substituted phenyl, C₆-C₁₈ aryl radical,N-pyrrolidonyl-C₁-C₄ alkyl, a monovalent radical of-alk-(OC₂H₄)_(m3)—OR″ (in which alk is C₁-C₆ alkyl diradical, R″ isC₁-C₄ alkyl, preferably methyl, and m3 is an integer from 1 to 10(preferably 1 to 5)), preferably R1 is methyl, ethyl, propyl,N-pyrrolidonyl-C₁-C₄ alkyl, a monovalent radical of-alk-(OC₂H₄)_(m3)—OR″ (in which alk is C₁-C₆ alkyl diradical, R″ isC₁-C₄ alkyl, preferably methyl, and m3 is an integer from 1 to 10(preferably 1 to 5)).

In this application, the term “polyoxazoline” refers to a linear polymerwhich is obtained in a ring-opening polymerization of one or moreoxazolines and generally has a formula of

in which: T1 and T2 are two terminal groups; R¹ is hydrogen, C₁-C₁₈alkyl, C₁-C₄ alkyl- substituted phenyl, C₁-C₄-alkoxy-substituted phenyl,C₆-C₁₈ aryl radical, N-pyrrolidonyl-C₁-C₄ alkyl, a monovalent radical of-alk-(OC₂H₄)_(m3)—OR″ (in which alk is C₁-C₆ alkyl diradical, R″ isC₁-C₄ alkyl, preferably methyl, and m3 is an integer from 1 to 10(preferably 1 to 5)), preferably R1 is methyl, ethyl, propyl,N-pyrrolidonyl-C₁-C₄ alkyl, a monovalent radical of-alk-(OC₂H₄)_(m3)—OR″ (in which alk is C₁-C₆ alkyl diradical, R″ isC₁-C₄ alkyl, preferably methyl, and m3 is an integer from 1 to 10(preferably 1 to 5)); x is an integer from 5 to 500. A polyoxazolinesegment has a divalent polymer chain of a formula of

in which R¹ and x are as defined above.

In this application, the term “poly(2-oxazoline-co-ethyleneimine)”refers to a statistical copolymer having a formula of

in which: T1 and T2 are terminal groups; R¹ is hydrogen, C₁-C₁₈ alkyl,C₁-C₄ alkyl- substituted phenyl, C₁-C₄-alkoxy-substituted phenyl, C₆-C₁₈aryl radical, N-pyrrolidonyl-C₁-C₄ alkyl, a monovalent radical of-alk-(OC₂H₄)_(m3)—OR″ (in which alk is C₁-C₆ alkyl diradical, R″ isC₁-C₄ alkyl, preferably methyl, and m3 is an integer from 1 to 10(preferably 1 to 5)), preferably R1 is methyl, ethyl, propyl,N-pyrrolidonyl-C₁-C₄ alkyl, a monovalent radical of-alk-(OC₂H₄)_(m3)—OR″ (in which alk is C₁-C₆ alkyl diradical, R″ isC₁-C₄ alkyl, preferably methyl, and m3 is an integer from 1 to 10(preferably 1 to 5)); x is an integer from 5 to 500; z is an integerequal to or less than x. A poly(2-oxazoline-co-ethyleneimine) isobtained by hydrolyzing a polyoxazoline.

In this application, the term“poly(2-oxazoline-co-ethyleneimine)-epichlorohydrin” refers to a polymerobtained by reacting a poly(2-oxazoline-co-ethyleneimine) withepichlorohydrin to convert all or substantial percentage (≧90%) of thesecondary amine groups of the poly(2-oxazoline-co-ethyleneimine) intoazetidinium groups.

In this application the term “azetidinium” or “3-hydroxyazetidinium”refers to a positively-charged, divalent radical (or group or moiety) of

in which ¹R and ²R are a hydrocarbon group.

The term “azlactone” refers to a mono-valent radical of formula

in which p is 0 or 1; ³R and ⁴R independently of each other is C₁-C₈alkyl (preferably methyl).

As used in this application, the term “phosphorylcholine” refers to amonovalent zwitterionic group of

in which t1 is an integer of 1 to 5 and R₁″, R₂″ and R₃″ independentlyof one another are C₁-C₈ alkyl or C₁-C₈ hydroxyalkyl.

As used in this application, the term “reactive vinylic monomer” refersto any vinylic monomer having at least one reactive functional groupselected from the group consisting of carboxyl group, primary aminogroup, and secondary amino group.

As used in this application, the term “non-reactive vinylic monomer”refers to any vinylic monomer (either hydrophilic or hydrophobic vinylicmonomer) free of carboxyl group, primary amino group, secondary aminogroup, epoxide group, isocyanate group, azlactone group, or aziridinegroup. A non-reactive vinylic monomer can include a hydroxyl group or atertiary or quaternium amino group.

A free radical initiator can be either a photoinitiator or a thermalinitiator. A “photoinitiator” refers to a chemical that initiates freeradical crosslinking/polymerizing reaction by the use of light. A“thermal initiator” refers to a chemical that initiates radicalcrosslinking/polymerizing reaction by the use of heat energy.

A “water contact angle” refers to an average water contact angle (i.e.,contact angles measured by Sessile Drop method) at the room temperature,which is obtained by averaging measurements of contact angles with atleast 3 individual contact lenses.

The term “intactness” in reference to a coating on a silicone hydrogelcontact lens is intended to describe the extent to which the contactlens can be stained by Sudan Black in a Sudan Black staining testdescribed in Example 1. Good intactness of the coating on a siliconehydrogel contact lens means that there is practically no Sudan Blackstaining of the contact lens.

The term “durability” in reference to a coating on a silicone hydrogelcontact lens is intended to describe that the coating on the siliconehydrogel contact lens can survive a digital rubbing test.

As used herein, “surviving a digital rubbing test” or “surviving adurability test” in reference to a coating on a contact lens means thatafter digitally rubbing the lens according to a procedure described inExample 1, water contact angle on the digitally rubbed lens is stillabout 100 degrees or less, preferably about 90 degrees or less, morepreferably about 80 degrees or less, most preferably about 70 degrees orless.

“Ophthalmically compatible”, as used herein, refers to a material orsurface of a material which may be in intimate contact with the ocularenvironment for an extended period of time without significantlydamaging the ocular environment and without significant user discomfort.

The term “ophthalmically safe” with respect to a packaging solution forsterilizing and storing contact lenses is meant that a contact lensstored in the solution is safe for direct placement on the eye withoutrinsing after autoclave and that the solution is safe and sufficientlycomfortable for daily contact with the eye via a contact lens. Anophthalmically-safe packaging solution after autoclave has a tonicityand a pH that are compatible with the eye and is substantially free ofocularly irritating or ocularly cytotoxic materials according tointernational ISO standards and U.S. FDA regulations.

The term “modulus” or “elastic modulus” in reference to a contact lensor a material means the tensile modulus or Young's modulus which is ameasure of the stiffness of a contact lens or a material. The moduluscan be measured using a method in accordance with ANSI Z80.20 standard.A person skilled in the art knows well how to determine the elasticmodulus of a silicone hydrogel material or a contact lens. For example,all commercial contact lenses have reported values of elastic modulus.

An “organic-based solution” refers to a solution which is a homogeneousmixture consisting of an organic-based solvent and one or more solutesdissolved in the organic based solvent. An organic-based coatingsolution refers to an organic-based solution containing at least onepolymeric coating material as a solute in the solution.

An “organic-based solvent” is intended to describe a solvent systemwhich consists of one or more organic solvents and optionally about 40%or less, preferably about 30% or less, more preferably about 20% orless, even more preferably about 10% or less, in particular about 5% orless by weight of water relative to the weight of the solvent system.

The invention is generally related topoly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymers (i.e., areaction product of poly(2-oxazoline-co-ethyleneimine) copolymers andepichlorohydrin) and chemically-modified derivatives thereof as well astheir uses in forming a non-silicone hydrogel coating on a contact lens(preferably a silicone hydrogel (SiHy) contact lens). Apoly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer of theinvention can be tailored to have desired degrees of hydrophilicity andreactivity by adjusting the amount of amide, amine, and azetidiniumgroups. Such azetidinium-containing copolymers can be used as ananchoring polymer and/or a water-soluble and thermally-reactivehydrophilic polymeric material for forming a hydrogel coating, accordingto thermally-induced reaction mechanism involving an azetidnium groupand a carboxyl, primary amino or secondary amino group as shown below:

in which X₁ is —S—*, —OC(═O)—*, or —NR′—* in which R′ is hydrogen, aC₁-C₂₀ unsubstituted or substituted, linear or branched alkyl group; *represents an organic radical. Such a reaction can be carried outconveniently and directly in a lens package during autoclave (i.e.,heating the lens package with the lens in a packaging solution about118° C. to about 125° C. for approximately 20-40 minutes under pressure)which is a commonly-used sterilization process in the contact lensindustry. Any azetidnium groups which are not reacted with carboxyl,primary amino or secondary amino groups will be hydrolyzed duringautoclave as shown below

The invention, in one aspect, provides apoly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer (or acopolymer), which comprises, consists essential of, or consists of:

-   -   (1)N-acyl-iminoethylene monomeric units in an amount (designated        as M1) of from about 2% to about 95% by mole, wherein the        N-acyl-iminoethylene monomeric units have a formula of

-   -    in which R¹ is (a) a monovalent radical R^(1a) which is        hydrogen, methyl, ethyl, propyl, isopropyl, N-pyrrolidonyl-C₁-C₄        alkyl, or a monovalent radical of -alk-(OC₂H₄)_(m3)—OR″ (in        which alk is C₁-C₆ alkyl diradical, R″ is C₁-C₄ alkyl,        preferably methyl, and m3 is an integer from 1 to 10 (preferably        1 to 5)), or (b) a monovalent radical R^(1b) which is C₄-C₁₈        alkyl, C₁-C₄ alkyl-substituted phenyl, C₁-C₄-alkoxy-substituted        phenyl, or C₆-C₁₈ aryl radical;    -   (2) azetidinium monomeric units in an amount (designated as M2)        of from about 0.5% to about 95% by mole, wherein the azetidinium        monomeric units have a formula of

-   -   (3) ethyleneimine monomeric units in an amount (designated as        M3) of from 0 to about 60% by mole, wherein the ethyleneimine        monomeric units have a formula of *—NH—CH₂—CH₂—*; and    -   (4) crosslink units in an amount (designated as M4) of from 0 to        about 5% by mole,    -   wherein the crosslink units have a formula of

provided that (M1+M2+M3+M4) is about 100%. It should be understood thata poly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer of theinvention can comprise two terminal groups which are not counted in thecalculation of the amounts of the units in the copolymer.

A poly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer of theinvention can be prepared from a poly(2-oxazoline) polymer (i.e., apoly(N-acyl-iminoethylene) which is obtained by polymerization ofoxazoline) according to a two-step process. In the first step, apoly(2-oxazoline) polymer is partially hydrolyzed under acidicconditions to form a poly(2-oxazoline-co-ethyleneimine) copolymer. Inthe second step, the resultant poly(2-oxazoline-co-ethyleneimine)copolymer can react with epichlorohydrin

in an amount sufficient to convert all or a percentage of ethyleneiminemonomeric units of the poly(2-oxazoline-co-ethyleneimine) copolymer intoazetidinium monomeric units, thereby forming apoly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer of theinvention. Where only a percentage of ethyleneimine monomeric units areconverted into azetidinium monomeric units, inter- and/orintra-crosslinks may be formed as results of reactions between oneazetidinium monomeric unit and one ethyleneimine monomeric unit withinone single copolymer molecule or between two copolymer molecules asshown below.

Partial hydrolysis of a poly(2-oxazoline) can be carried out accordingto commonly used hydrolysis methods, for examples, such as, thosedisclosed by De la Rosa and co-workers in Polymer Chemistry, 2014, DOI;by Jeong and coworker in J. of Controlled Release 2001, 73, 391-399; orby Fernandes and coworkers in International Journal of Nanomedicine2013, 13(8), 4091-4102 (all of which are incorporated by reference intheir entireties). As taught by De la Rosa and coworker in their paper,control over the desired degree of hydrolysis of poly(2-oxazoline) canbe achieved by selecting the appropriate HCl concentration.

The secondary amine groups of one or more ethyleneimine monomeric unitsof the resultant poly(2-oxazoline-co-ethyleneimine) copolymer can beconverted into azetidinium groups by a reaction with epichlorohydrin,under conditions well known to a person skilled in the art, for example,those disclosed by Chattopadhyay, Keul and Moeller in MacromolecularChemistry and Physics 2012, 213, 500-512; by Obokata, Yanagisawa andIsogai in J. Applied Polym. Sci. 2005, 97, 2249-2255, both of which areincorporated by reference in their entireties).

Poly(2-methyl-oxazoline), poly(2-ethyl-oxazoline),poly(2-propyl-oxazoline) polymers with various molecular weights arecommercially available. Other poly(2-oxazoline) can be prepared from oneor more 2-oxazoline monomers according to cationic ring openingpolymerization (CROP) using a microwave synthesizer (see, T. X. Viegaset al., Bioconjugate Chemistry, 2011, 22, 976-986; R. Hoogenboom et al.,Journal of Combinatorial Chemistry, 2004, 7, 10-13; F. Wiesbrock et al.,Macromolecules, 2005, 38, 5025-5034). Block poly(2-oxazoline) copolymerscan be prepared from two or more different 2-oxazoline monomers bysequential one-pot monomer addition.

2-oxazoline monomer can be prepared from their corresponding nitrilesaccording to the procedures disclosed in the published articles, suchas, H. White, W. Seeliger, Liebigs Ann. Chem. 1974, 996; W. Seeliger, E.Aufderhaar, W. Diepers, R. Feinauer, R. Nehring, W. Thier, Hellman,Angew. Chem. 1966, 20, 913; and K. Lüdtke, R. Jordan, P. Hommes, O.Nuyken, C. Naumann, Macromol. Biosci. 2005, 5, 384-393 (hereinincorporated by references in their entireties). For example, a2-oxazoline of formula

in which R¹ is N-pyrrolidonylethyl

3-methoxyethyleneglycol-propyl (CH₃—OCH₂CH₂O—C₃H₆—), or3-methoxytriethyleneglycol-propyl [CH₃—O—(CH₂CH₂O)₃—C₃H₆—] can beprepared according the procedures disclosed by Lüdtke and coworker(Macromol. Biosci. 2005, 5, 384-393).

Scheme IV illustrates a procedure to prepare apoly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer of theinvention.

It should be understood that the two terminal groups of apoly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer can bepresent in the copolymer due to the use ofcationic-ring-opening-polymerization initiator and terminator in itspreparation and are not shown in Scheme IV.

In a preferred embodiment, apoly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer of theinvention comprises hydrophilic N-acyl-iminoethylene monomeric units offormula

in which R^(1a) is hydrogen, methyl, ethyl, propyl, isopropyl,N-pyrrolidonyl-C₁-C₄ alkyl, or a monovalent radical of-alk-(OC₂H₄)_(m3)—OR″ (in which alk is C₁-C₆ alkyl diradical, R″ isC₁-C₄ alkyl, preferably methyl, and m3 is an integer from 1 to 10(preferably 1 to 5)).

In another preferred embodiment, apoly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer of theinvention comprises hydrophobic N-acyl-iminoethylene monomeric units offormula

in which R^(1b) is C₆-C₁₈ alkyl, C₁-C₄ alkyl-substituted phenyl,C₁-C₄-alkoxy-substituted phenyl, or C₆-C₁₈ aryl radical.

In another preferred embodiment, apoly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer of theinvention comprises: hydrophobic N-acyl-iminoethylene monomeric units offormula

in which R^(1b) is C₆-C₁₈ alkyl, C₁-C₄ alkyl-substituted phenyl,C₁-C₄-alkoxy-substituted phenyl, or C₆-C₁₈ aryl radical; and hydrophilicN-acyl-iminoethylene monomeric units of formula

in which R^(1a) is hydrogen, methyl, ethyl, propyl, isopropyl,N-pyrrolidonyl-C₁-C₄ alkyl, or a monovalent radical of-alk-(OC₂H₄)_(m3)—OR″ (in which alk is C₁-C₆ alkyl diradical, R″ isC₁-C₄ alkyl, preferably methyl, and m3 is an integer from 1 to 10(preferably 1 to 5)).

In various preferred embodiments of the invention, apoly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer of theinvention comprises: (1) from about 10% to about 85%, preferably fromabout 20% to about 75%, even more preferably from about 30% to about65%, by mole of N-acyl-iminoethylene monomeric units; (2) from about2.5% to about 75%, preferably from about 5% to about 75%, even morepreferably from about 10% to about 60%, by mole of azetidinium monomericunits; (3) from 0% to about 60%, preferably from 0% to about 30%, evenmore preferably from 0 to about 10%, by mole of ethyleneimine monomericunits; and (4) from 0 to about 5%, preferably from 0 to about 2.5%, evenmore preferably from 0 to about 1%, by mole of crosslink units. It isunderstood that these various preferred embodiments of the inventionencompass various combinations of one preferred or even more preferredembodiment of one composition component (e.g., component (1), (2), (3)or (4)) can be combined with the preferred or even more preferredembodiments of other composition components).

The weight average molecular weight M_(w) of apoly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer of theinvention is at least about 500 Daltons, preferably from about 1,000 toabout 5,000,000 Daltons, more preferably from about 5,000 to about2,000,000 Daltons, even more preferably from about 10,000 to about1,000,000 Daltons.

A poly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer of theinvention can find particular use in forming non-silicone hydrogelcoatings on silicone hydrogel contact lenses and/or in forming ananchoring prime coating on silicone hydrogel contact lenses.

Where a poly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer ofthe invention comprises hydrophobic N-acyl-iminoethylene monomeric unitsof formula

in which R^(1b) is C₆-C₁₈ alkyl, C₁-C₄ alkyl-substituted phenyl,C₁-C₄-alkoxy-substituted phenyl, or C₆-C₁₈ aryl radical, such acopolymer can be used as an anchoring prime coating on silicone hydrogelcontact lenses through hydrophobic-hydrophobic interactions with thehydrophobic silicone hydrogel materials at and near the surface of thesilicone hydrogel contact lenses.

Where a poly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer ofthe invention comprises hydrophilic N-acyl-iminoethylene monomeric unitsof formula

in which R^(1a) is methyl, ethyl, propyl, N-pyrrolidonyl-C₁-C₄ alkyl, amonovalent radical of -alk-(OC₂H₄)_(m3)—OR″ (in which alk is C₁-C₆ alkyldiradical, R″ is C₁-C₄ alkyl, preferably methyl, and m3 is an integerfrom 1 to 10 (preferably 1 to 5)), such a copolymer can be used as acoating material for forming a hydrogel coating on top of an anchoringcoating (layer) on a silicone hydrogel contact lens.

Where a poly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer ofthe invention comprises both (a) hydrophobic N-acyl-iminoethylenemonomeric units of formula

in which R^(1b) is C₆-C₁₈ alkyl, C₁-C₄ alkyl-substituted phenyl,C₁-C₄-alkoxy-substituted phenyl, or C₆-C₁₈ aryl radical and (b)hydrophilic N-acyl-iminoethylene monomeric units of formula

in which R^(1a) is methyl, ethyl, propyl, N-pyrrolidonyl-C₁-C₄ alkyl, amonovalent radical of -alk-(OC₂H₄)_(m3)—OR″ (in which alk is C₁-C₆ alkyldiradical, R″ is C₁-C₄ alkyl, preferably methyl, and m3 is an integerfrom 1 to 10 (preferably 1 to 5)), such a copolymer is an amphiphiliccopolymer which can be used as a coating material for forming a hydrogelcoating directly on a silicone hydrogel contact lens.

A poly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer of theinvention can find particular use in forming a water-soluble andthermally crosslinkable hydrophilic polymeric material containingazetidinium groups. Such a water-soluble and thermally crosslinkablehydrophilic polymeric material can be obtained by chemically modifyingpoly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer of theinvention with a hydrophilicity-enhancing agent having at least onereactive functional group selected from the group consisting of aminogroup, carboxyl group, thiol group, and combination thereof and can beespecially useful for forming relatively-thick and soft non-siliconehydrogel coatings on contact lenses, preferably hydrogel contact lenses,more preferably silicone hydrogel contact lenses.

The invention, in another aspect, provides a water-soluble andthermally-crosslinkable hydrophilic polymeric material which comprises:azetidinium groups; from about 5% to about 95%, preferably from about10% to about 90%, more preferably from about 15% to about 85%, by weightof first polymer chains derived from apoly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer of any oneof claims 1 to 6; and from about 5% to about 95%, preferably from about10% to about 90%, even more preferably from about 15% to about 85%, byweight of hydrophilic moieties or second polymer chains derived from atleast one hydrophilicity-enhancing agent having at least one reactivefunctional group selected from the group consisting of primary aminogroup, secondary amino group, carboxyl group, thiol group, andcombination thereof. The composition of the hydrophilic polymericmaterial is determined by the composition (based on the total weight ofthe reactants) of a reactants mixture used for preparing thethermally-crosslinkable hydrophilic polymeric material according to thecrosslinking reactions shown in Scheme I above. For example, if areactant mixture comprises about 75% by weight of apoly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer of theinvention and about 25% by weight of at least onehydrophilicity-enhancing agent based on the total weight of thereactants, then the resultant hydrophilic polymeric material compriseabout 75% by weight of first polymer chains derived from thepoly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer of theinvention and about 25% by weight of hydrophilic moieties or secondpolymer chains derived from said at least one hydrophilicity-enhancingagent. The azetidinium groups of the thermally-crosslinkable hydrophilicpolymeric material are those azetidinium groups (of theepichlorohydrin-functionalized polyamine or polyamidoamine) which do notparticipate in crosslinking reactions for preparing thethermally-crosslinkable hydrophilic polymeric material.

Any suitable hydrophilicity-enhancing agents can be used in theinvention so long as they contain at least one amino group, at least onecarboxyl group, and/or at least one thiol group.

A preferred class of hydrophilicity-enhancing agents include withoutlimitation: primary amino-, secondary amino-, carboxyl- orthiol-containing monosaccharides (e.g., 3-amino-1,2-propanediol,1-thiolglycerol, 5-keto-D-gluconic acid, galactosamine, glucosamine,galacturonic acid, gluconic acid, glucosaminic acid, mannosamine,saccharic acid 1,4-lactone, saccharide acid, Ketodeoxynonulosonic acid,N-methyl-D-glucamine, 1-amino-1-deoxy-β-D-galactose,1-amino-1-deoxysorbitol, 1-methylamino-1-deoxysorbitol, N-aminoethylgluconamide); primary amino-, secondary amino-, carboxyl- orthiol-containing disaccharides (e.g., chondroitin disaccharide sodiumsalt, di(β-D-xylopyranosyl)amine, digalacturonic acid, heparindisaccharide, hyaluronic acid disaccharide, Lactobionic acid); andprimary amino-, secondary amino-, carboxyl- or thiol-containingoligosaccharides (e.g., carboxymethyl-β-cyclodextrin sodium salt,trigalacturonic acid); and combinations thereof.

Another preferred class of hydrophilicity-enhancing agents ishydrophilic polymers having one or more (primary or secondary) amino,carboxyl and/or thiol groups. More preferably, the content of the amino(—NHR′ with R′ as defined above), carboxyl (—COOH) and/or thiol (—SH)groups in a hydrophilic polymer as a hydrophilicity-enhancing agent isless than about 40%, preferably less than about 30%, more preferablyless than about 20%, even more preferably less than about 10%, by weightbased on the total weight of the hydrophilic polymer.

One preferred class of hydrophilic polymers as hydrophilicity-enhancingagents are (primary or secondary) amino- or carboxyl-containingpolysaccharides, for example, such as, carboxymethylcellulose (having acarboxyl content of about 40% or less, which is estimated based on thecomposition of repeating units, —[C₆H_(10-m)O₅(CH₂CO₂H)_(m)]— in which mis 1 to 3), carboxyethylcellulose (having a carboxyl content of about36% or less, which is estimated based on the composition of repeatingunits, —[C₆H_(10-m)O₅(C₂H₄CO₂H)_(m)]— in which m is 1 to 3)carboxypropylcellulose (having a carboxyl content of about 32% or less,which is estimated based on the composition of repeating units,—[C₆H_(10-m)O₅(C₃H₆CO₂H)_(m)]—, in which m is 1 to 3), hyaluronic acid(having a carboxyl content of about 11%, which is estimated based on thecomposition of repeating units, —(C₁₃H₂₀O₉NCO₂H)—), chondroitin sulfate(having a carboxyl content of about 9.8%, which is estimated based onthe composition of repeating units, (C₁₂H₁₈O₁₃NSCO₂H)—), or combinationsthereof.

Another preferred class of hydrophilic polymers ashydrophilicity-enhancing agents include without limitation:poly(ethylene glycol) (PEG) with mono-amino (primary or secondaryamino), carboxyl or thiol group (e.g., PEG-NH₂, PEG-SH, PEG-COOH);H₂N-PEG-NH₂; HOOC-PEG-COOH; HS-PEG-SH; H₂N-PEG-COOH; HOOC-PEG-SH;H₂N-PEG-SH; multi-arm PEG with one or more amino (primary or secondary),carboxyl or thiol groups; PEG dendrimers with one or more amino (primaryor secondary), carboxyl or thiol groups; a diamino-(primary orsecondary) or dicarboxyl-terminated homo- or co-polymer of anon-reactive hydrophilic vinylic monomer; a monoamino- (primary orsecondary) or monocarboxyl-terminated homo- or co-polymer of anon-reactive hydrophilic vinylic monomer; a copolymer which is apolymerization product of a composition comprising (1) about 60% byweight or less, preferably from about 0.1% to about 30%, more preferablyfrom about 0.5% to about 20%, even more preferably from about 1% toabout 15%, by weight of one or more reactive vinylic monomers and (2) atleast one non-reactive hydrophilic vinylic monomer; and combinationsthereof. Reactive vinylic monomer(s) and non-reactive hydrophilicvinylic monomer(s) are those described previously.

More preferably, a hydrophilic polymer as a hydrophilicity-enhancingagent is PEG-NH₂; PEG-SH; PEG-COOH; H₂N-PEG-NH₂; HOOC-PEG-COOH;HS-PEG-SH; H₂N-PEG-COOH; HOOC-PEG-SH; H₂N-PEG-SH; multi-arm PEG with oneor more amino, carboxyl or thiol groups; PEG dendrimers with one or moreamino, carboxyl or thiol groups; a monoamino-, monocarboxyl-, diamino-or dicarboxyl-terminated homo- or copolymer of a non-reactivehydrophilic vinylic monomer selected from the group consisting ofacryamide (AAm), N,N-dimethylacrylamide (DMA), N-vinylpyrrolidone (NVP),N-vinyl-N-methyl acetamide, glycerol (meth)acrylate, hydroxyethyl(meth)acrylate, N-hydroxyethyl (meth)acrylamide, C₁-C₄-alkoxypolyethylene glycol (meth)acrylate having a weight average molecularweight of up to 400 Daltons, vinyl alcohol,N-methyl-3-methylene-2-pyrrolidone, 1-methyl-5-methylene-2-pyrrolidone,5-methyl-3-methylene-2-pyrrolidone, N,N-dimethylaminoethyl(meth)acrylate, N,N-dimethylaminopropyl(metha)crylamide,(meth)acryloyloxyethyl phosphorylcholine, and combinations thereof; acopolymer which is a polymerization product of a composition comprising(1) from about 0.1% to about 30%, preferably from about 0.5% to about20%, more preferably from about 1% to about 15%, by weight of acrylicacid, C₁-C₃ alkylacrylic acid, allylamine and/or amino-C₂-C₄ alkyl(meth)acrylate, and (2) at least one non-reactive hydrophilic vinylicmonomer selected from the group consisting of acryamide,N,N-dimethylacrylamide, N-vinylpyrrolidone, (meth)acryloyloxyethylphosphorylcholine, N-vinyl-N-methyl acetamide, glycerol (meth)acrylate,hydroxyethyl (meth)acrylate, N-hydroxyethyl (meth)acrylamide,C₁-C₄-alkoxy polyethylene glycol (meth)acrylate having a weight averagemolecular weight of up to 400 Daltons, vinyl alcohol, and combinationthereof.

Most preferably, the hydrophilicity-enhancing agent as ahydrophilicity-enhancing agent is PEG-NH₂; PEG-SH; PEG-COOH; monoamino-,monocarboxyl-, diamino- or dicarboxyl-terminated polyvinylpyrrolidone;monoamino-, monocarboxyl-, diamino- or dicarboxyl-terminatedpolyacrylamide; monoamino-, monocarboxyl-, diamino- ordicarboxyl-terminated poly(DMA); monoamino- or monocarboxyl-, diamino-or dicarboxyl-terminated poly(DMA-co-NVP); monoamino-, monocarboxyl-,diamino- or dicarboxyl-terminated poly(NVP-co-N,N-dimethylaminoethyl(meth)acrylate)); monoamino-, monocarboxyl-, diamino- ordicarboxyl-terminated poly(vinylalcohol); monoamino-, monocarboxyl-,diamino- or dicarboxyl-terminated poly[(meth)acryloyloxyethylphosphrylcholine] homopolymer or copolymer; monoamino-, monocarboxyl-,diamino- or dicarboxyl-terminated poly(NVP-co-vinyl alcohol);monoamino-, monocarboxyl-, diamino- or dicarboxyl-terminatedpoly(DMA-co-vinyl alcohol); poly[(meth)acrylic acid-co-acrylamide] withfrom about 0.1% to about 30%, preferably from about 0.5% to about 20%,more preferably from about 1% to about 15%, by weight of (meth)acrylicacid; poly[(meth)acrylic acid-co-NVP) with from about 0.1% to about 30%,preferably from about 0.5% to about 20%, more preferably from about 1%to about 15%, by weight of (meth)acrylic acid; a copolymer which is apolymerization product of a composition comprising (1)(meth)acryloyloxyethyl phosphorylcholine and (2) from about 0.1% toabout 30%, preferably from about 0.5% to about 20%, more preferably fromabout 1% to about 15%, by weight of acrylic acid, C₁-C₃ alkylacrylicacid, allylamine and/or amino-C₂-C₄alkyl (meth)acrylate; and combinationthereof.

PEGs with functional groups and multi-arm PEGs with functional groupscan be obtained from various commercial suppliers, e.g., Polyscience,and Shearwater Polymers, inc., etc.

Monoamino-, monocarboxyl-, diamino- or dicarboxyl-terminated homo- orcopolymers of one or more non-reactive hydrophilic vinylic monomers orof a phosphorylcholine-containing vinylic monomer can be preparedaccording to procedures described in U.S. Pat. No. 6,218,508, hereinincorporated by reference in its entirety. For example, to prepare adiamino- or dicarboxyl-terminated homo- or co-polymer of a non-reactivehydrophilic vinylic monomer, the non-reactive vinylic monomer, a chaintransfer agent with an amino or carboxyl group (e.g.,2-aminoethanethiol, 2-mercaptopropinic acid, thioglycolic acid,thiolactic acid, or other hydroxymercaptanes, aminomercaptans, orcarboxyl-containing mercaptanes) and optionally other vinylic monomerare copolymerized (thermally or actinically) with a reactive vinylicmonomer (having an amino or carboxyl group), in the presence of anfree-radical initiator. Generally, the molar ratio of chain transferagent to that of all of vinylic monomers other than the reactive vinylicmonomer is from about 1:5 to about 1:100, whereas the molar ratio ofchain transfer agent to the reactive vinylic monomer is 1:1. In suchpreparation, the chain transfer agent with amino or carboxyl group isused to control the molecular weight of the resultant hydrophilicpolymer and forms a terminal end of the resultant hydrophilic polymer soas to provide the resultant hydrophilic polymer with one terminal aminoor carboxyl group, while the reactive vinylic monomer provides the otherterminal carboxyl or amino group to the resultant hydrophilic polymer.Similarly, to prepare a monoamino- or monocarboxyl-terminated homo- orco-polymer of a non-reactive hydrophilic vinylic monomer, thenon-reactive vinylic monomer, a chain transfer agent with an amino orcarboxyl group (e.g., 2-aminoethanethiol, 2-mercaptopropinic acid,thioglycolic acid, thiolactic acid, or other hydroxymercaptanes,aminomercaptans, or carboxyl-containing mercaptanes) and optionallyother vinylic monomers are copolymerized (thermally or actinically) inthe absence of any reactive vinylic monomer.

As used herein, a copolymer of a non-reactive hydrophilic vinylicmonomer refers to a polymerization product of a non-reactive hydrophilicvinylic monomer with one or more additional vinylic monomers. Copolymerscomprising a non-reactive hydrophilic vinylic monomer and a reactivevinylic monomer (e.g., a carboxyl-containing vinylic monomer, a primaryamino group-containing vinylic monomer or a secondary aminogroup-containing vinylic monomer) can be prepared according to anywell-known radical polymerization methods or obtained from commercialsuppliers. Copolymers containing methacryloyloxyethyl phosphorylcholineand carboxyl-containing vinylic monomer (or amino-containing vinylicmonomer) can be obtained from NOP Corporation (e.g., LIPIDURE®-A and-AF).

The weight average molecular weight M_(w) of the hydrophilic polymerhaving at least one amino, carboxyl or thiol group (as ahydrophilicity-enhancing agent) is preferably from about 500 to about1,000,000, more preferably from about 1,000 to about 500,000, even morepreferably from about 5,000 to about 250,000 Daltons.

In accordance with the invention, the reaction between ahydrophilicity-enhancing agent and apoly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer of theinvention is carried out at a temperature of from about 40° C. to about100° C. for a period of time sufficient (from about 0.3 hour to about 24hours, preferably from about 1 hour to about 12 hours, even morepreferably from about 2 hours to about 8 hours) to form a water-solubleand thermally-crosslinkable hydrophilic polymeric material containingazetidinium groups.

In accordance with the invention, the concentration of ahydrophilicity-enhancing agent relative to apoly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer of theinvention must be selected not to render a resultant hydrophilicpolymeric material water-insoluble (i.e., a solubility of less than0.005 g per 100 ml of water at room temperature) and not to consume morethan about 99%, preferably about 98%, more preferably about 97%, evenmore preferably about 96% of the azetidinium groups of thepoly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer of theinvention.

The invention, in a further aspect, provides methods for producingcoated contact lenses (preferably hydrogel contact lenses, morepreferably silicone hydrogel contact lenses) each having a crosslinkedhydrophilic coating thereon, involving use of at least apoly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer of theinvention fully described above and/or at least one water-soluble andthermally crosslinkable hydrophilic polymeric material of the inventionfully described above.

One method of the invention for producing coated contact lenses(preferably hydrogel contact lenses, more preferably silicone hydrogelcontact lenses) each having a crosslinked hydrophilic coating thereoncomprises the steps of: (a) obtaining a contact lens (preferably ahydrogel contact lens, more preferably a silicone hydrogel contact lens)and a poly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer ofthe invention as described above (incorporated herein in its entirety),wherein the contact lens comprises, on and/or near the surface of thecontact lens, reactive functional groups selected from the groupconsisting of primary amino groups, secondary amino groups, carboxylgroups, and combinations thereof; and (b) heating the contact lens in anaqueous solution in the presence of thepoly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer to and at atemperature from about 40° C. to about 140° C. for a period of timesufficient to covalently attach thepoly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer onto thesurface of the contact lens through covalent linkages each formedbetween one azetidinium group of thepoly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer and one ofthe reactive functional groups on and/or near the surface of the contactlens, thereby forming a crosslinked hydrophilic coating on the contactlens.

Another method of the invention for producing coated contact lenses(preferably hydrogel contact lenses, more preferably silicone hydrogelcontact lenses) each having a crosslinked hydrophilic coating thereoncomprises the steps of: (a) obtaining a contact lens (preferably ahydrogel contact lens, more preferably a silicone hydrogel contactlens); (b) applying a layer of apoly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer of theinvention to form an anchoring coating on the contact lens, wherein thepoly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer compriseshydrophobic N-acyl-iminoethylene monomeric units as described above((incorporated herein in its entirety); and (c) heating the contact lenshaving the anchoring coating thereon in an aqueous solution to and at atemperature from about 40° C. to about 140° C. in the presence of awater-soluble hydrophilic polymer having reactive functional groupsselected from the group consisting of primary amino groups, secondaryamino groups, carboxyl groups, thiol groups, and combinations thereof,for a period of time sufficient to covalently attach the hydrophilicpolymer onto the surface of the contact lens through covalent linkageseach formed between one azetidinium group of the anchoring coating andone of the reactive functional groups of the hydrophilic polymer,thereby forming a crosslinked hydrophilic coating on the contact lens.

A further method of the invention for producing coated contact lenses(preferably hydrogel contact lenses, more preferably silicone hydrogelcontact lenses) each having a crosslinked hydrophilic coating thereoncomprises the steps of: (a) obtaining a contact lens (preferably ahydrogel contact lens, more preferably a silicone hydrogel contact lens)and a water-soluble and thermally-crosslinkable hydrophilic polymericmaterial of the invention as described above (incorporated herein in itsentirety), wherein the contact lens comprises, on and/or near thesurface of the contact lens, reactive functional groups selected fromthe group consisting of primary amino groups, secondary amino groups,carboxyl groups, and combinations thereof; and (b) heating the contactlens in an aqueous solution in the presence of the water-soluble andthermally-crosslinkable hydrophilic polymeric material to and at atemperature from about 40° C. to about 140° C. for a period of timesufficient to covalently attach the hydrophilic polymeric material ontothe surface of the contact lens through covalent linkages each formedbetween one azetidinium group of thepoly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer and one ofthe reactive functional groups on and/or near the surface of the contactlens, thereby forming a crosslinked hydrophilic coating on the contactlens.

A person skilled in the art knows very well how to make contact lenses.For example, contact lenses can be produced in a conventional“spin-casting mold,” as described for example in U.S. Pat. No.3,408,429, or by the full cast-molding process in a static form, asdescribed in U.S. Pat. Nos. 4,347,198; 5,508,317; 5,583,463; 5,789,464;and 5,849,810, or by lathe cutting of silicone hydrogel buttons as usedin making customized contact lenses. In cast-molding, a lens formulationtypically is dispensed into molds and cured (i.e., polymerized and/orcrosslinked) in molds for making contact lenses. For producing hydrogelcontact lenses, a hydrogel lens formulation comprises at least onehydrophilic vinylic monomer. For production of silicone hydrogel (SiHy)contact lenses, a SiHy lens-forming composition (or SiHy lensformulation) for cast-molding or spin-cast molding or for making SiHyrods used in lathe-cutting of contact lenses generally comprises atleast one components selected from the group consisting of asilicone-containing vinylic monomer, a silicone-containing vinylicmacromer, a silicone-containing prepolymer, a hydrophilic vinylicmonomer, a hydrophobic vinylic monomer, a crosslinking agent (a compoundhaving a molecular weight of about 700 Daltons or less and containing atleast two ethylenically unsaturated groups), a free-radical initiator(photoinitiator or thermal initiator), a hydrophilic vinylicmacromer/prepolymer, and combination thereof, as well known to a personskilled in the art. A SiHy contact lens formulation can also compriseother necessary components known to a person skilled in the art, suchas, for example, a UV-absorbing agent, a visibility tinting agent (e.g.,dyes, pigments, or mixtures thereof), antimicrobial agents (e.g.,preferably silver nanoparticles), a bioactive agent, leachablelubricants, leachable tear-stabilizing agents, and mixtures thereof, asknown to a person skilled in the art. Resultant SiHy contact lenses thencan be subjected to extraction with an extraction solvent to removeunpolymerized components from the resultant lenses and to hydrationprocess, as known by a person skilled in the art. In addition, apreformed SiHy contact lens can be a colored contact lens (i.e., a SiHycontact lens having at least one colored patterns printed thereon aswell known to a person skilled in the art).

Numerous SiHy lens formulations including various combinations ofcomponents described above have been described in numerous patents andpatent applications published by the filing date of this application.All of them can be used in obtaining a SiHy lens to be coated. A SiHylens formulation for making commercial SiHy lenses, such as, lotrafilconA, lotrafilcon B, delefilcon A, balafilcon A, galyfilcon A, senofilconA, narafilcon A, narafilcon B, comfilcon A, enfilcon A, asmofilcon A, orthe like, can also be used in making SiHy contact lenses to be coated inthis invention.

In accordance with the invention, a contact lens (preferably a hydrogelcontact lens, more preferably a silicone hydrogel contact lens) caninherently comprise reactive functional groups (primary amino groups,secondary amino groups, and/or carboxyl groups) on and/or near itssurface, or can be free of but be modified to comprise reactivefunctional groups (primary amino groups, secondary amino groups, and/orcarboxyl groups) on and/or near its surface.

Where a contact lens (preferably a hydrogel contact lens, morepreferably a silicone hydrogel contact lens) inherently comprisesreactive functional groups (primary amino groups, secondary aminogroups, and/or carboxyl groups) on and/or near its surface, it isobtained by polymerizing a lens formulation comprising a reactivevinylic monomer (i.e., a vinylic monomer having a reactive functionalgroup selected from the group consisting of primary amino group,secondary amino group, and carboxyl group).

Examples of preferred reactive vinylic monomers include withoutlimitation amino-C₂-C₆ alkyl (meth)acrylate, C₁-C₆ alkylamino-C₂-C₆alkyl (meth)acrylate, allylamine, vinylamine, amino-C₂-C₆ alkyl(meth)acrylamide, C₁-C₆ alkylamino-C₂-C₆ alkyl (meth)acrylamide, acrylicacid, C₁-C₄ alkylacrylic acid (e.g., methacrylic ethylacrylic acid,propylacrylic acid, butylacrylic acid), N,N-2-acrylamidoglycolic acid,beta methyl-acrylic acid (crotonic acid), alpha-phenyl acrylic acid,beta-acryloxy propionic acid, sorbic acid, angelic acid, cinnamic acid,1-carboxy-4-phenyl butadiene-1,3, itaconic acid, citraconic acid,mesaconic acid, glutaconic acid, aconitic acid, maleic acid, fumaricacid, tricarboxy ethylene, and combinations thereof. Preferably, thesilicone hydrogel contact lens is made from a lens formulationcomprising at least one reactive vinylic monomer selected from the groupconsisting of amino-C₂-C₆ alkyl (meth)acrylate, C₁-C₆ alkylamino-C₂-C₆alkyl (meth)acrylate, allylamine, vinylamine, amino-C₁-C₆ alkyl(meth)acrylamide, C₁-C₆ alkylamino-C₂-C₆ alkyl (meth)acrylamide, acrylicacid, C₁-C₆ alkylacrylic acid, N,N-2-acrylamidoglycolic acid, andcombinations thereof. The lens formulation comprises preferably fromabout 0.1% to about 10%, more preferably from about 0.25% to about 7%,even more preferably from about 0.5% to about 5%, most preferably fromabout 0.75% to about 3%, by weight of the reactive vinylic monomer.

A contact lens can also be subjected either to a surface treatment toform a reactive base coating having amino groups and/or carboxyl groupson the surface of the contact lens. Examples of surface treatmentsinclude without limitation a surface treatment by energy (e.g., aplasma, a static electrical charge, irradiation, or other energysource), chemical treatments, chemical vapor deposition, the grafting ofhydrophilic vinylic monomers or macromers onto the surface of anarticle, layer-by-layer coating (“LbL coating”) obtained according tomethods described in U.S. Pat. Nos. 6,451,871, 6,719,929, 6,793,973,6,811,805, and 6,896,926 and in U.S. Patent Application Publication Nos.2007/0229758A1, 2008/0152800A1, and 2008/0226922A1, (herein incorporatedby references in their entireties). “LbL coating”, as used herein,refers to a coating that is not covalently attached to the polymermatrix of a contact lens and is obtained through a layer-by-layer(“LbL”) deposition of charged or chargeable (by protonation ordeprotonation) and/or non-charged materials on the lens. An LbL coatingcan be composed of one or more layers.

Preferably, the surface treatment is an LbL coating process. In thispreferred embodiment (i.e., the reactive LbL base coating embodiment), aresultant contact lens comprises a reactive LbL base coating includingat least one layer of a reactive polymer (i.e., a polymer having pendantreactive functional groups such as primary amino groups, secondary aminogroups, and/or carboxyl groups), wherein the reactive LbL base coatingis obtained by contacting the contact lens with a coating solution of areactive polymer. Contacting of a contact lens with a coating solutionof a reactive polymer can occur by dipping it into the coating solutionor by spraying it with the coating solution. One contacting processinvolves solely dipping the contact lens in a bath of a coating solutionfor a period of time or alternatively dipping the contact lenssequentially in a series of bath of coating solutions for a fixedshorter time period for each bath. Another contacting process involvessolely spray a coating solution. However, a number of alternativesinvolve various combinations of spraying- and dipping- steps may bedesigned by a person having ordinary skill in the art. The contactingtime of a contact lens with a coating solution of a reactive polymer maylast up to about 10 minutes, preferably from about 5 to about 360seconds, more preferably from about 5 to about 250 seconds, even morepreferably from about 5 to about 200 seconds.

In accordance with this reactive LbL base coating embodiment, thereactive polymer can be a linear or branched polymer having pendantreactive functional groups (primary amino groups, secondary aminogroups, and/or carboxyl groups). Any polymers having pendant reactivefunctional groups (primary amino groups, secondary amino groups, and/orcarboxyl groups) can be used as a reactive polymer for forming basecoatings on silicone hydrogel contact lenses. Examples of such reactivepolymers include without limitation: a homopolymer of a reactive vinylicmonomer; a copolymer of two or more reactive vinylic monomers; acopolymer of a reactive vinylic monomer with one or more non-reactivehydrophilic vinylic monomers (i.e., hydrophilic vinylic monomers free ofany carboxyl or (primary or secondary) amino group); polyethyleneimine(PEI); polyvinylalcohol with pendant amino groups; a carboxyl-containingcellulose (e.g., carboxymethylcellulose, carboxyethylcellulose,carboxypropylcellulose); hyaluronate; chondroitin sulfate; poly(glutamicacid); poly(aspartic acid); and combinations thereof.

Preferred reactive vinylic monomers are those described previously.

Preferred examples of non-reactive hydrophilic vinylic monomers free ofcarboxyl or amino group include without limitation acrylamide (AAm),methacrylamide N,N-dimethylacrylamide (DMA), N,N-dimethylmethacrylamide(DMMA), N-vinylpyrrolidone (NVP), N,N,-dimethylaminoethylmethacrylate(DMAEM), N,N-dimethylaminoethylacrylate (DMAEA),N,N-dimethylaminopropylmethacrylamide (DMAPMAm),N,N-dimethylaminopropylacrylamide (DMAPAAm), glycerol methacrylate,3-acryloylamino-1-propanol, N-hydroxyethyl acrylamide,N-[tris(hydroxymethyl)methyl]-acrylamide,N-methyl-3-methylene-2-pyrrolidone, 1-ethyl-3-methylene-2-pyrrolidone,1-methyl-5-methylene-2-pyrrolidone, 1-ethyl-5-methylene-2-pyrrolidone,5-methyl-3-methylene-2-pyrrolidone, 5-ethyl-3-methylene-2-pyrrolidone,2-hydroxyethyl (meth)acrylate, hydroxypropyl (meth)acrylate,C₁-C₄-alkoxy polyethylene glycol (meth)acrylate having a weight averagemolecular weight of up to 1500 Daltons, N-vinyl formamide, N-vinylacetamide, N-vinyl isopropylamide, N-vinyl-N-methyl acetamide, allylalcohol, vinyl alcohol (hydrolyzed form of vinyl acetate in thecopolymer), a phosphorylcholine-containing vinylic monomer (including(meth)acryloyloxyethyl phosphorylcholine and those described in U.S.Pat. No. 5,461,433, herein incorporated by reference in its entirety),and combinations thereof.

Preferably, the reactive polymers for forming a reactive LbL basecoating are polyacrylic acid, polymethacrylic acid, polyethylacrylicacid, polypropylacrylic acid, poly(N,N-2-acrylamidoglycolic acid),poly[(meth)acrylic acid-co-acrylamide], poly[(meth)acrylic acid-co-vinylpyrrolidone], hydrolyzed poly[(meth)acrylic acid-co-vinylacetate],polyethyleneimine (PEI), polyallylamine hydrochloride (PAH) homo- orcopolymer, polyvinylamine homo- or copolymer, or combinations thereof.

The weight average molecular weight M_(w) of a reactive polymer forforming a reactive LbL base coating is at least about 10,000 Daltons,preferably at least about 50,000 Daltons, more preferably at least about100,000 Daltons, even more preferably from about 500,000 to 5,000,000Daltons.

A solution of a reactive polymer for forming a reactive LbL base coatingon contact lenses can be prepared by dissolving one or more reactivepolymers in water, a mixture of water and an organic solvent misciblewith water, an organic solvent, or a mixture of one or more organicsolvent. Preferably, the reactive polymer is dissolved in a mixture ofwater and one or more organic solvents, an organic solvent, or a mixtureof one or more organic solvent. It is believed that a solvent systemcontaining at least one organic solvent can swell a contact lens(preferably hydrogel contact lens, more preferably a silicone hydrogelcontact lens) so that a portion of the reactive polymer may penetrateinto the contact lens and increase the durability of the reactive basecoating.

Any organic solvents can be used in preparation of a solution of thereactive polymer. Examples of organic solvents include withoutlimitation tetrahydrofuran, tripropylene glycol methyl ether,dipropylene glycol methyl ether, ethylene glycol n-butyl ether, ketones(e.g., acetone, methyl ethyl ketone, etc.), diethylene glycol n-butylether, diethylene glycol methyl ether, ethylene glycol phenyl ether,propylene glycol methyl ether, propylene glycol methyl ether acetate,dipropylene glycol methyl ether acetate, propylene glycol n-propylether, dipropylene glycol n-propyl ether, tripropylene glycol n-butylether, propylene glycol n-butyl ether, dipropylene glycol n-butyl ether,tripropylene glycol n-butyl ether, propylene glycol phenyl etherdipropylene glycol dimethyl ether, polyethylene glycols, polypropyleneglycols, ethyl acetate, butyl acetate, amyl acetate, methyl lactate,ethyl lactate, i-propyl lactate, methylene chloride, methanol, ethanol,1- or 2-propanol, 1- or 2-butanol, tert-butanol, tert-amyl alcohol,menthol, cyclohexanol, cyclopentanol and exonorborneol, 2-pentanol,3-pentanol, 2-hexanol, 3-hexanol, 3-methyl-2-butanol, 2-heptanol,2-octanol, 2-nonanol, 2-decanol, 3-octanol, norborneol,2-methyl-2-pentanol, 2,3-dimethyl-2-butanol, 3-methyl-3-pentanol,1-methylcyclohexanol, 2-methyl-2-hexanol, 3,7-dimethyl-3-octanol,1-chloro-2-methyl-2-propanol, 2-methyl-2-heptanol, 2-methyl-2-octanol,2-2-methyl-2-nonanol, 2-methyl-2-decanol, 3-methyl-3-hexanol,3-methyl-3-heptanol, 4-methyl-4-heptanol, 3-methyl-3-octanol,4-methyl-4-octanol, 3-methyl-3-nonanol, 4-methyl-4-nonanol,3-methyl-3-octanol, 3-ethyl-3-hexanol, 3-methyl-3-heptanol,4-ethyl-4-heptanol, 4-propyl-4-heptanol, 4-isopropyl-4-heptanol,2,4-dimethyl-2-pentanol, 1-methylcyclopentanol, 1-ethylcyclopentanol,1-ethylcyclopentanol, 3-hydroxy-3-methyl-1-butene,4-hydroxy-4-methyl-1-cyclopentanol, 2-phenyl-2-propanol,2-methoxy-2-methyl-2-propanol 2,3,4-trimethyl-3-pentanol,3,7-dimethyl-3-octanol, 2-phenyl-2-butanol, 2-methyl-1-phenyl-2-propanoland 3-ethyl-3-pentanol, 1-ethoxy-2-propanol, 1-methyl-2-pyrrolidone,N,N-dimethylpropionamide, dimethyl formamide, dimethyl acetamide,dimethyl propionamide, N-methyl pyrrolidinone, and mixtures thereof.

In another preferred embodiment, a contact lens (preferably a hydrogelcontact lens, more preferably a silicone hydrogel contact lens)comprises inherently reactive functional groups (primary amino groups,secondary amino groups, and/or carboxyl groups) on and/or near itssurface and is further subjected to a surface treatment to form areactive LbL base coating having reactive functional groups therein.

In another preferred embodiment (reactive plasma base coating), acontact lens (preferably a hydrogel contact lens, more preferably asilicone hydrogel contact lens) is subjected to a plasma treatment toform a covalently-attached reactive plasma base coating on the contactlens, i.e., polymerizing one or more reactive vinylic monomers (any oneof those described previously) under the effect of plasma generated byelectric discharge (so-called plasma-induced polymerization). The term“plasma” denotes an ionized gas, e.g. created by electric glow dischargewhich may be composed of electrons, ions of either polarity, gas atomsand molecules in the ground or any higher state of any form ofexcitation, as well as of photons. It is often called “low temperatureplasma”. For a review of plasma polymerization and its uses reference ismade to R. Hartmann “Plasma polymerisation: Grundlagen, Technik andAnwendung, Jahrb. Oberflächentechnik (1993) 49, pp. 283-296,Battelle-Inst. e.V. Frankfurt/Main Germany; H. Yasuda, “Glow DischargePolymerization”, Journal of Polymer Science: Macromolecular Reviews,vol. 16 (1981), pp. 199-293; H. Yasuda, “Plasma Polymerization”,Academic Press, Inc. (1985); Frank Jansen, “Plasma DepositionProcesses”, in “Plasma Deposited Thin Films”, ed. by T. Mort and F.Jansen, CRC Press Boca Raton (19); O. Auciello et al. (ed.)“Plasma-Surface Interactions and Processing of Materials” publ. byKluwer Academic Publishers in NATO ASI Series; Series E: AppliedSciences, vol. 176 (1990), pp. 377-399; and N. Dilsiz and G. Akovali“Plasma Polymerization of Selected Organic Compounds”, Polymer, vol. 37(1996) pp. 333-341. Preferably, the plasma-induced polymerization is an“after-glow” plasma-induced polymerization as described in WO98028026(herein incorporated by reference in its entirety). For “after-glow”plasma polymerization the surface of a contact lens is treated firstwith a non-polymerizable plasma gas (e.g. H2, He or Ar) and then in asubsequent step the surface thus activated is exposed to a vinylicmonomer having an amino group or carboxyl group (any reactive vinylicmonomer described above), while the plasma power having been switchedoff. The activation results in the plasma-induced formation of radicalson the surface which in the subsequent step initiate the polymerizationof the vinylic monomer thereon.

In accordance with the invention, an anchoring coating on a contact lens(preferably a hydrogel contact lens, more preferably a silicone hydrogelcontact lens) is formed by contacting a contact lens (to be coated) witha solution of a poly(2-oxazoline-co-ethyleneimine)-epichlorohydrincopolymer comprising hydrophobic N-acyl-iminoethylene monomeric units asdescribed above (incorporated herein in its entirety). Contacting of thecontact lens with a coating solution of apoly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer comprisinghydrophobic N-acyl-iminoethylene monomeric units can occur by dipping itinto the coating solution or by spraying it with the coating solution.One contacting process involves solely dipping the contact lens in abath of a solution of the anchoring polymer for a period of time oralternatively dipping the contact lens sequentially in a series of bathof solutions of the anchoring polymer for a fixed shorter time periodfor each bath. Another contacting process involves solely spray asolution of the anchoring polymer. However, a number of alternativesinvolve various combinations of spraying—and dipping—steps may bedesigned by a person having ordinary skill in the art. The contactingtime of a contact lens with a solution of the anchoring polymer may lastup to about 10 minutes, preferably from about 5 to about 360 seconds,more preferably from about 5 to about 250 seconds, even more preferablyfrom about 5 to 200 seconds. A coating solution of apoly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer comprisinghydrophobic N-acyl-iminoethylene monomeric units can be prepared bydissolving it in an organic solvent, a mixture of two or more organicsolvents, a mixture of water with one or more organic solvent. It isbelieved that a solvent system containing at least one organic solventcan swell a silicone hydrogel contact lens so that a portion of thepoly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer comprisinghydrophobic N-acyl-iminoethylene monomeric units may penetrate into thecontact lens and increase the durability of the anchoring coating. Anyorganic solvent described above can be used in preparing a coatingsolution of a poly(2-oxazoline-co-ethyleneimine)-epichlorohydrincopolymer comprising hydrophobic N-acyl-iminoethylene monomeric units.

In accordance with this aspect of the invention, the step of heating isperformed preferably by autoclaving the contact lens (preferablyhydrogel contact lens, more preferably silicone hydrogel contact lens)immersed in a packaging solution (i.e., a buffered aqueous solution) ina sealed lens package at a temperature of from about 118° C. to about125° C. for approximately 20-90 minutes. In accordance with thisembodiment of the invention, the packaging solution is a bufferedaqueous solution which is ophthalmically safe after autoclave.

Lens packages (or containers) are well known to a person skilled in theart for autoclaving and storing a soft contact lens. Any lens packagescan be used in the invention. Preferably, a lens package is a blisterpackage which comprises a base and a cover, wherein the cover isdetachably sealed to the base, wherein the base includes a cavity forreceiving a sterile packaging solution and the contact lens.

Lenses are packaged in individual packages, sealed, and sterilized(e.g., by autoclave at about 120° C. or higher for at least 30 minutesunder pressure) prior to dispensing to users. A person skilled in theart will understand well how to seal and sterilize lens packages.

In accordance with the invention, a packaging solution contains at leastone buffering agent and one or more other ingredients known to a personskilled in the art. Examples of other ingredients include withoutlimitation, tonicity agents, surfactants, antibacterial agents,preservatives, and lubricants (e.g., cellulose derivatives, polyvinylalcohol, polyvinyl pyrrolidone).

The packaging solution contains a buffering agent in an amountsufficient to maintain a pH of the packaging solution in the desiredrange, for example, preferably in a physiologically acceptable range ofabout 6 to about 8.5. Any known, physiologically compatible bufferingagents can be used. Suitable buffering agents as a constituent of thecontact lens care composition according to the invention are known tothe person skilled in the art. Examples are boric acid, borates, e.g.sodium borate, citric acid, citrates, e.g. potassium citrate,bicarbonates, e.g. sodium bicarbonate, TRIS(2-amino-2-hydroxymethyl-1,3-propanediol), Bis-Tris(Bis-(2-hydroxyethyl)-imino-tris-(hydroxymethyl)-methane),bis-aminopolyols, triethanolamine, ACES(N-(2-hydroxyethyl)-2-aminoethanesulfonic acid), BES(N,N-Bis(2-hydroxyethyl)-2-aminoethanesulfonic acid), HEPES(4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid), MES(2-(N-morpholino)ethanesulfonic acid), MOPS(3-[N-morpholino]-propanesulfonic acid), PIPES(piperazine-N,N′-bis(2-ethanesulfonic acid), TES(N-[Tris(hydroxymethyl)methyl]-2-aminoethanesulfonic acid), saltsthereof, phosphate buffers, e.g. Na₂HPO₄, NaH₂PO₄, and KH₂PO₄ ormixtures thereof. A preferred bis-aminopolyol is1,3-bis(tris[hydroxymethyl]-methylamino)propane (bis-TRIS-propane). Theamount of each buffer agent in a packaging solution is preferably from0.001% to 2%, preferably from 0.01% to 1%; most preferably from about0.05% to about 0.30% by weight.

The packaging solution has a tonicity of from about 200 to about 450milliosmol (mOsm), preferably from about 250 to about 350 mOsm. Thetonicity of a packaging solution can be adjusted by adding organic orinorganic substances which affect the tonicity. Suitable occularlyacceptable tonicity agents include, but are not limited to sodiumchloride, potassium chloride, glycerol, propylene glycol, polyols,mannitols, sorbitol, xylitol and mixtures thereof.

A packaging solution of the invention has a viscosity of from about 1centipoise to about 8 centipoises, more preferably from about 1.5centipoises to about 5 centipoises, at 25° C.

In a preferred embodiment, the packaging solution comprises preferablyfrom about 0.01% to about 2%, more preferably from about 0.05% to about1.5%, even more preferably from about 0.1% to about 1%, most preferablyfrom about 0.2% to about 0.5%, by weight of apoly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer of theinvention or a thermally-crosslinkable hydrophilic polymeric material ofthe invention.

In another preferred embodiment, a method of the invention can furthercomprise, before the step of heating, the steps of: contacting at roomtemperature the contact lens (preferably hydrogel contact lens, morepreferably silicone hydrogel contact lens) with an aqueous solution ofthe thermally-crosslinkable hydrophilic polymeric material to form a toplayer (i.e., an LbL coating) of thepoly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer or thethermally-crosslinkable hydrophilic polymeric material on the surface ofthe contact lens, immersing the contact lens with the top layer of thethermally-crosslinkable hydrophilic polymeric material in a packagingsolution in a lens package; sealing the lens package; and autoclavingthe lens package with the contact lens therein to form a crosslinkedhydrophilic coating on the contact lens.

A contact lens (preferably a hydrogel contact lens, more preferably asilicone hydrogel contact lens) obtained according to a method of theinvention has a surface hydrophilicity/wettability characterized byhaving an averaged water contact angle of preferably about 90 degrees orless, more preferably about 80 degrees or less, even more preferablyabout 70 degrees or less, most preferably about 60 degrees or less.

A silicone hydrogel contact lens obtained according to a method of theinvention has one property selected from the group consisting of: anoxygen permeability of at least about 40 barrers, preferably at leastabout 50 barrers, more preferably at least about 60 barrers, even morepreferably at least about 70 barrers; an elastic modulus of about 1.5MPa or less, preferably about 1.2 MPa or less, more preferably about 1.0or less, even more preferably from about 0.3 MPa to about 1.0 MPa; awater content of from about 15% to about 70%, preferably from about 20%to about 65%, more preferably from about 25% to about 60%, even morepreferably from about 30% to about 55% by weight when fully hydrated; acoating durability characterized by surviving a digital rubbing test andcombination thereof; and combinations thereof.

The water content of a silicone hydrogel contact lens can be measuredaccording to Bulk Technique as disclosed in U.S. Pat. No. 5,849,811.

The intrinsic “oxygen permeability”, Dk, of a material is the rate atwhich oxygen will pass through a material. As used in this application,the term “oxygen permeability (Dk)” in reference to a hydrogel (siliconeor non-silicone) or a contact lens means a measured oxygen permeability(Dk) which is corrected for the surface resistance to oxygen flux causedby the boundary layer effect according to the procedures described inExample 1 of 2012/0026457 A1 (herein incorporated by reference in itsentirety). Oxygen permeability is conventionally expressed in units ofbarrers, where “barrer” is defined as [(cm³ oxygen)(mm)/(cm²)(sec)(mmHg)]×10⁻¹⁰.

The “oxygen transmissibility”, Dk/t, of a lens or material is the rateat which oxygen will pass through a specific lens or material with anaverage thickness of t [in units of mm] over the area being measured.Oxygen transmissibility is conventionally expressed in units ofbarrers/mm, where “barrers/mm” is defined as [(cm³ oxygen)/(cm²)(sec)(mmHg)]×10⁻⁹.

Although various embodiments of the invention have been described usingspecific terms, devices, and methods, such description is forillustrative purposes only. The words used are words of descriptionrather than of limitation. It is to be understood that changes andvariations may be made by those skilled in the art without departingfrom the spirit or scope of the present invention, which is set forth inthe following claims. In addition, it should be understood that aspectsof the various embodiments may be interchanged either in whole or inpart or can be combined in any manner and/or used together, asillustrated below:

-   1. A poly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer,    comprising:    -   (1) N-acyl-iminoethylene monomeric units in an amount        (designated as M1) of from about 2% to about 95% by mole,        wherein the N-acyl-iminoethylene monomeric units have a formula        of

-   -    in which R¹ is        -   (a) a monovalent radical R^(1a) which is hydrogen, methyl,            ethyl, propyl, isopropyl, N-pyrrolidonyl-C₁-C₄ alkyl, or a            monovalent radical of -alk-(OC₂H₄)_(m3)—OR″ in which alk is            C₁-C₆ alkyl diradical, R″ is C₁-C₄ alkyl, and m3 is an            integer from 1 to 10, or        -   (b) a monovalent radical R^(1b) which is C₄-C₁₈ alkyl, C₁-C₄            alkyl-substituted phenyl, C₁-C₄-alkoxy-substituted phenyl,            or C₆-C₁₈ aryl radical;    -   (2) azetidinium monomeric units in an amount (designated as M2)        of from about 0.5% to about 95% by mole, wherein the azetidinium        monomeric units have a formula of

-   -   (3) ethyleneimine monomeric units in an amount (designated as        M3) of from 0 to about 60% by mole, wherein the ethyleneimine        monomeric units have a formula of *—NH—CH₂—CH₂—*; and    -   (4) crosslink units in an amount (designated as M4) of from 0 to        about 5% by mole, wherein the crosslink units have a formula of

-   -    provided that (M1+M2+M3+M4) is about 100%.

-   2. The poly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer    according to invention 1, wherein the    poly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer    comprises hydrophilic N-acyl-iminoethylene monomeric units of    formula

-    in which R^(1a) is hydrogen, methyl, ethyl, propyl, isopropyl,    N-pyrrolidonyl-C₁-C₄ alkyl, or a monovalent radical of    -alk-(OC₂H₄)_(m3)—OR″ in which alk is C₁-C₆ alkyl diradical, R″ is    C₁-C₄ alkyl, (preferably methyl), and m3 is an integer from 1 to 10    (preferably 1 to 5).-   3. The poly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer    according to invention 1 or 2, wherein R″ is methyl).-   4. The poly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer    according to invention 1, 2 or 3, wherein m3 is an integer from 1 to    5.-   5. The poly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer    according to invention 1, wherein the    poly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer    comprises hydrophobic N-acyl-iminoethylene monomeric units of    formula

-    in which R^(1b) is C₆-C₁₈ alkyl, C₁-C₄ alkyl-substituted phenyl,    C₁-C₄-alkoxy-substituted phenyl, or C₆-C₁₈ aryl radical.-   6. The poly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer    according to invention 1, wherein the    poly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer    comprises: hydrophobic N-acyl-iminoethylene monomeric units of    formula

-    in which R^(1b) is C₆-C₁₈ alkyl, C₁-C₄ alkyl-substituted phenyl,    C₁-C₄-alkoxy-substituted phenyl, or C₆-C₁₈ aryl radical; and    hydrophilic N-acyl-iminoethylene monomeric units of formula

-    in which R^(1a) is hydrogen, methyl, ethyl, propyl, isopropyl,    N-pyrrolidonyl-C₁-C₄ alkyl, or a monovalent radical of    -alk-(OC₂H₄)_(m3)—OR″ (in which alk is C₁-C₆ alkyl diradical, R″ is    C₁-C₄ alkyl, preferably methyl, and m3 is an integer from 1 to 10    (preferably 1 to 5)).-   7. The poly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer    according to any one of inventions 1 to 6, wherein the    poly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer    comprises: (1) from about 10% to about 85%, preferably from about    20% to about 75%, even more preferably from about 30% to about 65%,    by mole of N-acyl-iminoethylene monomeric units; (2) from about 2.5%    to about 75%, preferably from about 5% to about 75%, even more    preferably from about 10% to about 60%, by mole of azetidinium    monomeric units; (3) from 0% to about 60%, preferably from 0% to    about 30%, even more preferably from 0 to about 10%, by mole of    ethyleneimine monomeric units; and (4) from 0 to about 5%,    preferably from 0 to about 2.5%, even more preferably from 0 to    about 1%, by mole of crosslink units.-   8. The poly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer    of invention 7, wherein the    poly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer    comprises from about 20% to about 75%, even more preferably from    about 30% to about 65%, by mole of N-acyl-iminoethylene monomeric    units.-   9. The poly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer    of invention 7 or 8, wherein the    poly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer    comprises from about 5% to about 75%, even more preferably from    about 10% to about 60%, by mole of azetidinium monomeric units.-   10. The poly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer    of invention 7, 8 or 9, wherein the    poly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer    comprises from 0% to about 30%, even more preferably from 0 to about    10%, by mole of ethyleneimine monomeric units; and (4) from 0 to    about 5%, preferably from 0 to about 2.5%, even more preferably from    0 to about 1%, by mole of crosslink units.-   11. The poly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer    according to any one of inventions 7 to 10, wherein the    poly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer    comprises from 0 to about 2.5%, even more preferably from 0 to about    1%, by mole of crosslink units.-   12. The poly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer    of any one of inventions 1 to 11, having a weight average molecular    weight Mw of at least about 500 Daltons, preferably from about 1,000    to about 5,000,000 Daltons, more preferably from about 5,000 to    about 2,000,000 Daltons, even more preferably from about 10,000 to    about 1,000,000 Daltons.-   13. A water-soluble and thermally crosslinkable hydrophilic    polymeric material, comprising: azetidnium groups; from about 5% to    about 95% by weight of first polymer chains derived from a    poly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer of any    one of inventions 1 to 12; and from about 5% to about 95% by weight    of hydrophilic moieties or second polymer chains derived from at    least one hydrophilicity-enhancing agent having at least one    reactive functional group selected from the group consisting of    primary amino group, secondary amino group, carboxyl group, thiol    group, and combination thereof.-   14. The water-soluble and thermally crosslinkable hydrophilic    polymeric material of invention 13, comprising from about 10% to    about 90%, more preferably from about 15% to about 85%, by weight of    the first polymer chains.-   15. The water-soluble and thermally crosslinkable hydrophilic    polymeric material of invention 13 or 14, comprising from about 10%    to about 90%, even more preferably from about 15% to about 85%, by    weight of the hydrophilic moieties or the second polymer chains.-   16. The water-soluble and thermally crosslinkable hydrophilic    polymeric material according to any one of inventions 13 to 15,    wherein the hydrophilicity-enhancing polymeric agent is a    hydrophilic polymers having one or more amino, carboxyl and/or thiol    groups, wherein the content of the amino, carboxyl and/or thiol    groups in the hydrophilic polymers as the hydrophilicity-enhancing    agent is less than about 40%, preferably less than about 30%, more    preferably less than about 20%, even more preferably less than about    10%, by weight based on the total weight of the hydrophilic polymer.-   17. The water-soluble and thermally crosslinkable hydrophilic    polymeric material of invention 16, wherein the hydrophilic polymer    as the hydrophilicity-enhancing agent is: PEG-NH₂; PEG-SH; PEG-COOH;    H₂N-PEG-NH₂; HOOC-PEG-COOH; HS-PEG-SH; H₂N-PEG-COOH; HOOC-PEG-SH;    H₂N-PEG-SH; multi-arm PEG with one or more amino, carboxyl or thiol    groups; PEG dendrimers with one or more amino, carboxyl or thiol    groups; a diamino-, dicarboxyl-, monoamino- or    monocarboxyl-terminated homo- or co-polymer of a non-reactive    hydrophilic vinylic monomer; a copolymer which is a polymerization    product of a composition comprising (1) about 60% by weight or less,    preferably from about 0.1% to about 30%, more preferably from about    0.5% to about 20%, even more preferably from about 1% to about 15%,    by weight of at least one reactive vinylic monomer and (2) at least    one non-reactive hydrophilic vinylic monomer; or combinations    thereof, wherein PEG is a polyethylene glycol segment-   18. The water-soluble and thermally crosslinkable hydrophilic    polymeric material of invention 17, wherein the reactive vinylic    monomer is selected from the group consisting of amino-C₁-C₆ alkyl    (meth)acrylate, C₁-C₆ alkylamino-C₁-C₆ alkyl (meth)acrylate,    allylamine, vinylamine, amino-C₁-C₆ alkyl (meth)acrylamide, C₁-C₆    alkylamino-C₁-C₆ alkyl (meth)acrylamide, acrylic acid, C₁-C₄    alkylacrylic acid, N,N-2-acrylamidoglycolic acid,    beta-methyl-acrylic acid, alpha-phenyl acrylic acid, beta-acryloxy    propionic acid, sorbic acid, angelic acid, cinnamic acid,    1-carboxy-4-phenyl butadiene-1,3, itaconic acid, citraconic acid,    mesaconic acid, glutaconic acid, aconitic acid, maleic acid, fumaric    acid, tricarboxy ethylene, and combinations thereof,    -   wherein the non-reactive vinylic monomer is selected from the        group consisting of acrylamide, methacrylamide,        N,N-dimethylacrylamide, N,N-dimethylmethacrylamide,        N-vinylpyrrolidone, N,N,-dimethylaminoethylmethacrylate,        N,N-dimethylaminoethylacrylate,        N,N-dimethylaminopropylmethacrylamide,        N,N-dimethylaminopropylacrylamide, glycerol methacrylate,        3-acryloylamino-1-propanol, N-hydroxyethyl acrylamide,        N-[tris(hydroxymethyl)methyl]-acrylamide,        N-methyl-3-methylene-2-pyrrolidone,        1-ethyl-3-methylene-2-pyrrolidone,        1-methyl-5-methylene-2-pyrrolidone,        1-ethyl-5-methylene-2-pyrrolidone,        5-methyl-3-methylene-2-pyrrolidone,        5-ethyl-3-methylene-2-pyrrolidone, 2-hydroxyethyl        (meth)acrylate, hydroxypropyl (meth)acrylate, a        phosphorylcholine-containing vinylic monomer, C₁-C₄-alkoxy        polyethylene glycol (meth)acrylate having a weight average        molecular weight of up to 1500 Daltons, N-vinyl formamide,        N-vinyl acetamide, N-vinyl isopropylamide, N-vinyl-N-methyl        acetamide, allyl alcohol, vinyl alcohol (hydrolyzed form of        vinyl acetate in the copolymer), and combinations thereof.-   19. The water-soluble and thermally crosslinkable hydrophilic    polymeric material of invention 18, wherein the hydrophilic polymer    as the hydrophilicity-enhancing agent is: PEG-NH₂; PEG-SH; PEG-COOH;    H₂N-PEG-NH₂; HOOC-PEG-COOH; HS-PEG-SH; H₂N-PEG-COOH; HOOC-PEG-SH;    H₂N-PEG-SH; multi-arm PEG with one or more amino, carboxyl or thiol    groups; PEG dendrimers with one or more amino, carboxyl or thiol    groups; a monoamino-, monocarboxyl-, diamino- or    dicarboxyl-terminated homo- or copolymer of a non-reactive    hydrophilic vinylic monomer selected from the group consisting of    acryamide, N,N-dimethylacrylamide, N-vinylpyrrolidone,    N-vinyl-N-methyl acetamide, glycerol (meth)acrylate, hydroxyethyl    (meth)acrylate, N-hydroxyethyl (meth)acrylamide,    (meth)acryloyloxyethyl phosphorylcholine, C₁-C₄-alkoxy polyethylene    glycol (meth)acrylate having a weight average molecular weight of up    to 400 Daltons, vinyl alcohol, N-methyl-3-methylene-2-pyrrolidone,    1-methyl-5-methylene-2-pyrrolidone,    5-methyl-3-methylene-2-pyrrolidone, N,N-dimethylaminoethyl    (meth)acrylate, N,N-dimethylaminopropyl(metha)crylamide, and    combination thereof; a copolymer which is a polymerization product    of a composition comprising (1) from about 0.1% to about 30%,    preferably from about 0.5% to about 20%, more preferably from about    1% to about 15%, by weight of (meth)acrylic acid, allylamine and/or    amino-C₁-C₄ alkyl (meth)acrylate, and (2) at least one non-reactive    hydrophilic vinylic monomer selected from the group consisting of    acryamide, N,N-dimethylacrylamide, N-vinylpyrrolidone,    N-vinyl-N-methyl acetamide, glycerol (meth)acrylate, hydroxyethyl    (meth)acrylate, N-hydroxyethyl (meth)acrylamide,    (meth)acryloyloxyethyl phosphorylcholine, C₁-C₄-alkoxy polyethylene    glycol (meth)acrylate having a weight average molecular weight of up    to 400 Daltons, vinyl alcohol, and combination thereof.-   20. The water-soluble and thermally crosslinkable hydrophilic    polymeric material of invention 18, wherein the hydrophilic polymer    as the hydrophilicity-enhancing agent is an amino- or    carboxyl-containing polysaccharide, hyaluronic acid, chondroitin    sulfate, and combinations thereof.-   21. The water-soluble and thermally crosslinkable hydrophilic    polymeric material of invention 16, wherein the    hydrophilicity-enhancing agent is: amino-, carboxyl- or    thiol-containing monosaccharides; amino-, carboxyl- or    thiol-containing disaccharides; and amino-, carboxyl- or    thiol-containing oligosaccharides.-   22. A method for producing coated contact lenses each having a    crosslinked hydrophilic coating thereon comprises the steps of:    -   (a) obtaining a contact lens and a        poly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer of        any one of inventions 1 to 12, wherein the contact lens        comprises, on and/or near the surface of the contact lens,        reactive functional groups selected from the group consisting of        primary amino groups, secondary amino groups, carboxyl groups,        and combinations thereof; and    -   (b) heating the contact lens in an aqueous solution in the        presence of the        poly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer to        and at a temperature from about 40° C. to about 140° C. for a        period of time sufficient to covalently attach the        poly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer        onto the surface of the contact lens through covalent linkages        each formed between one azetidinium group of the        poly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer and        one of the reactive functional groups on and/or near the surface        of the contact lens, thereby forming a crosslinked hydrophilic        coating on the contact lens.-   23. The method of invention 22, wherein the contact lenses are    silicone hydrogel contact lenses.-   24. A method for producing coated contact lenses each having a    crosslinked hydrophilic coating thereon comprises the steps of:    -   (a) obtaining a contact lens;    -   (b) applying a layer of a        poly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer of        invention 5 or 6 to form an anchoring coating on the silicone        hydrogel contact lens, wherein the        poly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer        comprises hydrophobic N-acyl-iminoethylene monomeric units; and    -   (c) heating the contact lens having the anchoring coating        thereon in an aqueous solution to and at a temperature from        about 40° C. to about 140° C. in the presence of a water-soluble        hydrophilic polymer having reactive functional groups selected        from the group consisting of primary amino groups, secondary        amino groups, carboxyl groups, thiol groups, and combinations        thereof, for a period of time sufficient to covalently attach        the hydrophilic polymer onto the surface of the contact lens        through covalent linkages each formed between one azetidinium        group of the anchoring coating and one of the reactive        functional groups of the hydrophilic polymer, thereby forming a        crosslinked hydrophilic coating on the contact lens.-   25. The method of invention 24, wherein the contact lenses are    silicone hydrogel contact lenses.-   26. The method of invention 24 or 25, wherein the step (b) is    carried out by dipping the contact lens into a coating solution of    the poly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer or    by spraying the contact lens with the coating solution.-   27. The method according to any one of inventions 24 to 26, wherein    the coating of the    poly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer is    prepared by dissolving the    poly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer in an    organic solvent, a mixture of two or more organic solvents, a    mixture of water with one or more organic solvent.-   28. A method for producing coated contact lenses each having a    crosslinked hydrophilic coating thereon comprises the steps of:    -   (a) obtaining a contact lens and a water-soluble and        thermally-crosslinkable hydrophilic polymeric material of any        one of claims 7 to 13, wherein the contact lens comprises, on        and/or near the surface of the contact lens, reactive functional        groups selected from the group consisting of primary amino        groups, secondary amino groups, carboxyl groups, and        combinations thereof; and    -   (b) heating the contact lens in an aqueous solution in the        presence of the water-soluble and thermally-crosslinkable        hydrophilic polymeric material to and at a temperature from        about 40° C. to about 140° C. for a period of time sufficient to        covalently attach the hydrophilic polymeric material onto the        surface of the contact lens through covalent linkages each        formed between one azetidinium group of the        poly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer and        one of the reactive functional groups on and/or near the surface        of the contact lens, thereby forming a crosslinked hydrophilic        coating on the contact lens.-   29. The method of any one of inventions 22 to 28, wherein the step    of heating is performed in a lens package containing the contact    lens immersed in a packaging solution, more preferably by    autoclaving the contact lens immersed in a packaging solution in a    sealed lens package at a temperature of from about 118° C. to about    125° C. for approximately 20-90 minutes to form the crosslinked    hydrophilic coating on the contact lens, wherein the packaging    solution comprises at least one buffering agent in an amount    sufficient to maintain a pH of from about 6.0 to about 8.5 and has a    tonicity of from about 200 to about 450 milliosmol (mOsm),    preferably from about 250 to about 350 mOsm and a viscosity of from    about 1 centipoise to about 20 centipoises, preferably from about    1.5 centipoises to about 10 centipoises, more preferably from about    2 centipoises to about 5 centipoises, at 25° C.-   30. The method of any one of inventions 22 to 29, wherein the    contact lens is made by polymerizing a lens formulation comprising    at least one reactive vinylic monomer selected from the group    consisting of: amino-C₁-C₆ alkyl (meth)acrylate, C₁-C₆    alkylamino-C₁-C₆ alkyl (meth)acrylate, allylamine, vinylamine,    amino-C₁-C₆ alkyl (meth)acrylamide, C₁-C₆ alkylamino-C₁-C₆ alkyl    (meth)acrylamide, acrylic acid, C₁-C₄ alkylacrylic acid,    N,N-2-acrylamidoglycolic acid, beta methyl-acrylic acid,    alpha-phenyl acrylic acid, beta-acryloxy propionic acid, sorbic    acid, angelic acid, cinnamic acid, 1-carboxy-4-phenyl butadiene-1,3,    itaconic acid, citraconic acid, mesaconic acid, glutaconic acid,    aconitic acid, maleic acid, fumaric acid, tricarboxy ethylene, and    combinations thereof.-   31. The method according to any one of inventions 22 to 29, wherein    the contact lens is made by polymerizing a lens formulation    comprising at least one reactive vinylic monomer selected from the    group consisting of: amino-C₁-C₆ alkyl (meth)acrylate, C₁-C₆    alkylamino-C₁-C₆ alkyl (meth)acrylate, allylamine, amino-C₁-C₆ alkyl    (meth)acrylamide, C₁-C₆ alkylamino-C₁-C₆ alkyl (meth)acrylamide,    acrylic acid, C₁-C₆ alkylacrylic acid, and combinations thereof.-   32. The method of invention 30 or 31, wherein the lens formulation    comprises from about 0.1% to about 10%, more preferably from about    0.25% to about 7%, even more preferably from about 0.5% to about 5%,    most preferably from about 0.75% to about 3%, by weight of the    reactive vinylic monomer.-   33. The method of any one of inventions 22-32, wherein the contact    lens comprises a reactive base coating including amino and/or    carboxyl groups.-   34. The method of invention 33, wherein the reactive base coating    comprises at least one layer of a reactive polymer having pendant    amino groups and/or carboxyl groups and is obtained by contacting    the silicone hydrogel contact lens with a solution of the reactive    polymer, wherein the reactive polymer is: a homopolymer of amino-C₁    to C₄ alkyl (meth)acrylamide, amino-C₁ to C₄ alkyl (meth)acrylate,    C₁ to C₄ alkylamino-C₁ to C₄ alkyl (meth)acrylamide, C₁ to C₄    alkylamino-C₁ to C₄ alkyl (meth)acrylate, allylamine, or vinylamine;    polyethyleneimine; a polyvinylalcohol with pendant amino groups; a    linear or branched polyacrylic acid; a homopolymer of C₁ to C₄    alkylacrylic acid; a copolymer of amino-C₁ to C₄ alkyl    (meth)acrylamide, amino-C₁ to C₄ alkyl (meth)acrylate, C₁ to C₄    alkylamino-C₁ to C₄ alkyl (meth)acrylamide, C₁ to C₄ alkylamino-C₁    to C₄ alkyl (meth)acrylate, acrylic acid, C₁ to C₄ alkylacrylic    acid, maleic acid, and/or fumaric acid, with at least one    non-reactive hydrophilic vinylic monomer (preferably selected from    the group consisting of acrylamide, N,N-dimethyl (meth)acrylamide,    N-vinylpyrrolidone, glycerol methacrylate, N,N-2-acrylamidoglycolic    acid, 3-acryloylamino-1-propanol, N-hydroxyethyl acrylamide,    N-[tris(hydroxymethyl)methyl]-acrylamide,    N-methyl-3-methylene-2-pyrrolidone,    1-ethyl-3-methylene-2-pyrrolidone,    1-methyl-5-methylene-2-pyrrolidone,    1-ethyl-5-methylene-2-pyrrolidone,    5-methyl-3-methylene-2-pyrrolidone,    5-ethyl-3-methylene-2-pyrrolidone,    1-n-propyl-3-methylene-2-pyrrolidone,    1-n-propyl-5-methylene-2-pyrrolidone,    1-isopropyl-3-methylene-2-pyrrolidone,    1-isopropyl-5-methylene-2-pyrrolidone,    1-n-butyl-3-methylene-2-pyrrolidone,    1-tert-butyl-3-methylene-2-pyrrolidone, 2-hydroxyethyl    (meth)acrylate, hydroxypropyl (meth)acrylate, (meth)acryloyloxyethyl    phosphorylcholine, C₁-C₄-alkoxy polyethylene glycol (meth)acrylate    having a weight average molecular weight of up to 1500 Daltons,    N-vinyl formamide, N-vinyl acetamide, N-vinyl isopropylamide,    N-vinyl-N-methyl acetamide, allyl alcohol, vinyl alcohol (hydrolyzed    form of vinyl acetate in the copolymer), and combination thereof); a    carboxyl-containing cellulose; hyaluronate; chondroitin sulfate;    poly(glutamic acid); poly(aspartic acid); or combinations thereof.-   35. The method of invention 34, wherein the reactive polymer for    forming a base coating is polyacrylic acid, polymethacrylic acid,    poly[(meth)acrylic acid-co-acrylamide], poly[(meth)acrylic    acid-co-vinyl pyrrolidone], hydrolyzed poly[(meth)acrylic    acid-co-vinylacetate], polyethyleneimine, polyallylamine homo- or    copolymer, polyvinylamine homo- or copolymer, or combinations    thereof.-   36. The method of invention 34 or 35, wherein the reactive polymer    is dissolved in a mixture of water and one or more organic solvents,    an organic solvent, or a mixture of one or more organic solvent.-   37. The method of invention 33, wherein the reactive base coating on    the contact lens is obtained by polymerizing at least one    amino-containing or carboxyl-containing vinylic monomer under the    effect of a plasma.-   38. A contact lens product obtained according to the method of any    one of inventions 22 to 37.-   39. The contact lens of invention 38, wherein the contact lens is a    silicone hydrogel contact lens that has at least one property    selected from the group consisting of: an oxygen permeability of at    least about 40 barrers, preferably at least about 50 barrers, more    preferably at least about 60 barrers, even more preferably at least    about 70 barrers; an elastic modulus of about 1.5 MPa or less,    preferably about 1.2 MPa or less, more preferably about 1.0 or less,    even more preferably from about 0.2 MPa to about 1.0 MPa; an    Ionoflux Diffusion Coefficient, D, of, at least about 1.5×10⁻⁶    mm²/min, preferably at least about 2.6×10⁻⁶ mm²/min, more preferably    at least about 6.4×10⁻⁶ mm²/min; a water content of from about 18%    to about 70%, preferably from about 20% to about 60% by weight when    fully hydrated; and combinations thereof.-   40. The contact lens of invention 38, wherein the contact lens is a    hydrogel contact lens that has at least one property selected from    the group consisting of: an elastic modulus of about 1.5 MPa or    less, preferably about 1.2 MPa or less, more preferably about 1.0 or    less, even more preferably from about 0.2 MPa to about 1.0 MPa; and    a water content of from about 18% to about 70%, preferably from    about 20% to about 60% by weight when fully hydrated; and    combinations thereof.

EXAMPLE 1

500 mL of DI water is added to a 3 liter round bottom flask. The flaskhas at least 3 necks. The center neck contains a glass stir rod andpaddle for stirring the formation. Another neck contains a refluxcondenser cooled to about 2° C. 100 grams of poly(2-ethyl-2-oxazoline)(PEOZO 50 kDa) is added to the flask over about 15 minutes whilestirring at about 150 rpm. After addition is complete, stirringcontinues until the PEOZO is completely dissolved. 1000 mL of 10% HCl isadded to the PEOZO solution over about 15 minutes with stirring. Thestir rate is increased to about 200 rpm. A thermocouple is added to thethird neck to monitor temperature. A heating mantle is used to heat thesolution up to the boiling point. This temperature of about 102° C. ismaintained for a specified period of time (1 to 7 hours). After thespecified time, the heating mantle is removed and the solution isallowed to cool. When the solution cools to less than 70° C.,neutralization can begin. 5N NaOH is added to the solution using anaddition funnel with stirring over at least 30 minutes. Addition stopswhen the pH reaches between 8 and 10. The solution is allowed to cool toroom temperature. The solution is filtered through 1 um filter paper.

EXAMPLE 2

The solution from Example 1 is purified by ultrafiltration using 3 kDaregenerated cellulose membranes from Millipore. The solution isconcentrated to about 2 liters, if necessary, and about 40 liters ofwater is collected as permeate through the filters. During thepurification pH should be adjusted to maintain a pH between 9 and 11.The conductivity of the permeate should also be less than 10 μS/cm atthe end. Some of the sample is then isolated by freeze-drying and usedfor ¹H NMR analysis. NMR is useful to determine purity and thepercentage of amide hydrolysis. Table 1 below shows the % amidehydrolyzed as function of reaction time as determined by ¹H NMR.

TABLE 1 Sample 3A 3B 3C 3D Reaction time (hours) 1 3 5 7 AmideHydrolysis (%) 32 76 89 92

EXAMPLE 3

This example illustrates how to preparepoly(2-oxazoline-co-ethylenimine)-epichlorohydrin copolymers accordingto procedures similar to what described in the paper of Obokata andcoworkers (J. Appl. Polym. Sci. 2005, 97, 2249, herein incorporated byreference in its entirety) and as illustrated in the following scheme.

A hydrolyzed polyoxazoline prepared in Example 2 is dissolved in anpolar solvent such as acetonitrile, tetrahydrofuran, 1,4-dioxane, wateror a combination of any of the two followed by adding desire amount ofepichlorhydrin from 5% to 100% according to the total amine content,preferred from 30% to 70%. The mixture is stirred in a desiredtemperature range from 0° C. to 70° C., preferred 20° C. to 30° C. for 1to 5 hours depending upon the applied reaction temperature. The mostdesired combination according to the current experimental results is 25°C. for 3 hours in which the epichlorhydrin is fully reacted to secondaryamine without having side reaction or further ring close reaction asdescribed in below.

After the epichlorhydrin is fully consumed, the reaction temperature iselevated to 40-60° C. and maintained at that temperature for about 2hours to form the azetidinium group. If it is desirable to have aslightly branched final product, the reaction can be extended at 60° C.which allows the residual secondary amine groups to react with the newlyformed azetidinum groups until the target architecture is achieved.

If needed, the reaction can be stopped by adding sulfuric acid andreducing the pH to about 3.

After the reaction is completed, the final product can be purified withultrafiltration followed with a pH adjustment to 3 and then storage atfrozen temperature until further usage.

What is claimed is:
 1. Apoly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer,comprising: (1) Hydrophobic N-acyl-iminoethylene monomeric units in anamount (designated as M1) of from about 2% to about 95% by mole, whereinthe N-acyl-iminoethylene monomer units have a formula of

where R1 is a monovalent radical R1b which is C₆-C₁₈ alkyl, C₁-C₄alkyl-substituted phenyl, C₁-C₄ alkoxy-substituted phenyl, or C₆-C₁₈aryl radical; and a monovalent radical R1a which is hydrogen, methyl,ethyl, propyl, isopropyl, N-pyrrolidonyl-C₁-C₄ alkyl, or a monovalentradical of-alk-(OC₂H₄)_(m3)—OR″ in which alk is C₁-C₆ alkyl diradical,R″ is C₁-C₄ alkyl, and m3 is an integer from 1 to 10; (2) azetidiniummonomeric units in an amount (designated as M2) of from about 0.5% toabout 95% by mole, wherein the azetidinium monomeric units have aformula of

(3) ethyleneimine monomeric units in an amount (designated as M3) offrom 0 to about 60% by mole, wherein the ethyleneimine monomeric unitshave a formula of *—NH—CH2—CH2—* and (4) crosslink units in an amount(designated as M4) of from 0 to about 5% by mole, wherein the crosslinkunits have a formula of

provided that (M1+M2+M3+M4) is about 100%.
 2. Thepoly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer of claim 1,wherein the poly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymercomprises hydrophilic N-acyl-iminoethylene monomeric units of formula

in which R^(1a) is hydrogen, methyl, ethyl, propyl, isopropyl,N-pyrrolidonyl-C₁-C₄ alkyl, or a monovalent radical of-alk-(OC₂H₄)_(m3)—OR″ in which alk is C₁-C₆ alkyl diradical, R″ is C₁-C₄alkyl, and m3 is an integer from 1 to
 10. 3. Thepoly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer of claim 1,wherein the poly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymercomprises hydrophobic N-acyl-iminoethylene monomeric units of formula

in which R^(1b) is C₆-C₁₈ alkyl, C₁-C₄ alkyl-substituted phenyl,C₁-C₄-alkoxy-substituted phenyl, or C₆-C₁₈ aryl radical.
 4. Thepoly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer of claim 1,wherein the poly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymercomprises: (1) from about 10% to about 85% by mole ofN-acyl-iminoethylene monomeric units; (2) from about 2.5% to about 75%by mole of azetidinium monomeric units; (3) from 0% to about 60% by moleof ethyleneimine monomeric units; and (4) from 0 to about 5% by mole ofcrosslink units.
 5. Thepoly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer of claim 4,having a weight average molecular weight Mw of at least about 500Daltons.
 6. The poly(2-oxazoline-co-ethyleneimine)-epichlorohydrincopolymer of claim 2, wherein R^(1a) is hydrogen or methyl.
 7. Thepoly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer of claim 2,wherein R^(1a) is ethyl, propyl, or isopropyl.
 8. Thepoly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer of claim 2,wherein R^(1a) is N-pyrrolidonyl-C₁-C₄ alkyl.
 9. Thepoly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer of claim 2,wherein R^(1a) is a monovalent radical of -alk-(OC₂H₄)_(m3)—OR″ in whichalk is C₁-C₆ alkyl diradical, R″ is C₁-C₄ alkyl, and m3 is an integerfrom 1 to
 10. 10. The poly(2-oxazoline-co-ethyleneimine)-epichlorohydrincopolymer of claim 2, wherein thepoly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer comprises:(1) from about 10% to about 85% by mole of N-acyl-iminoethylenemonomeric units; (2) from about 2.5% to about 75% by mole of azetidiniummonomeric units; (3) from 0% to about 60% by mole of ethyleneiminemonomeric units; and (4) from 0 to about 5% by mole of crosslink units.11. The poly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer ofclaim 10, having a weight average molecular weight Mw of at least about500 Daltons.
 12. The poly(2-oxazoline-co-ethyleneimine)-epichlorohydrincopolymer of claim 6, wherein thepoly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer comprises:(1) from about 10% to about 85% by mole of N-acyl-iminoethylenemonomeric units; (2) from about 2.5% to about 75% by mole of azetidiniummonomeric units; (3) from 0% to about 60% by mole of ethyleneiminemonomeric units; and (4) from 0 to about 5% by mole of crosslink units.13. The poly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer ofclaim 12, having a weight average molecular weight Mw of at least about500 Daltons.
 14. The poly(2-oxazoline-co-ethyleneimine)-epichlorohydrincopolymer of claim 7, wherein thepoly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer comprises:(1) from about 10% to about 85% by mole of N-acyl-iminoethylenemonomeric units; (2) from about 2.5% to about 75% by mole of azetidiniummonomeric units; (3) from 0% to about 60% by mole of ethyleneiminemonomeric units; and (4) from 0 to about 5% by mole of crosslink units.15. The poly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer ofclaim 14, having a weight average molecular weight Mw of at least about500 Daltons.
 16. The poly(2-oxazoline-co-ethyleneimine)-epichlorohydrincopolymer of claim 8, wherein thepoly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer comprises:(1) from about 10% to about 85% by mole of N-acyl-iminoethylenemonomeric units; (2) from about 2.5% to about 75% by mole of azetidiniummonomeric units; (3) from 0% to about 60% by mole of ethyleneiminemonomeric units; and (4) from 0 to about 5% by mole of crosslink units.17. The poly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer ofclaim 16, having a weight average molecular weight Mw of at least about500 Daltons.
 18. The poly(2-oxazoline-co-ethyleneimine)-epichlorohydrincopolymer of claim 9, wherein thepoly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer comprises:(1) from about 10% to about 85% by mole of N-acyl-iminoethylenemonomeric units; (2) from about 2.5% to about 75% by mole of azetidiniummonomeric units; (3) from 0% to about 60% by mole of ethyleneiminemonomeric units; and (4) from 0 to about 5% by mole of crosslink units.19. The poly(2-oxazoline-co-ethyleneimine)-epichlorohydrin copolymer ofclaim 18, having a weight average molecular weight Mw of at least about500 Daltons.